WO2021081277A1 - Dosing regimens for treating or preventing c5-associated diseases - Google Patents

Dosing regimens for treating or preventing c5-associated diseases Download PDF

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Publication number
WO2021081277A1
WO2021081277A1 PCT/US2020/056981 US2020056981W WO2021081277A1 WO 2021081277 A1 WO2021081277 A1 WO 2021081277A1 US 2020056981 W US2020056981 W US 2020056981W WO 2021081277 A1 WO2021081277 A1 WO 2021081277A1
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seq
amino acid
acid sequence
set forth
sequence set
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PCT/US2020/056981
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English (en)
French (fr)
Inventor
John Davis
Albert Thomas DICIOCCIO
Olivier HARARI
Kuan-Ju Lin
Andrew Rankin
Ronda RIPPLEY
Jonathan WEYNE
George Yancopoulos
Feng Yang
Yi Zhang
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Regeneron Pharmaceuticals, Inc.
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Priority to CN202080089231.8A priority Critical patent/CN115052889A/zh
Priority to EP20807598.6A priority patent/EP4048691A1/en
Priority to MX2022004712A priority patent/MX2022004712A/es
Priority to CA3153195A priority patent/CA3153195A1/en
Priority to KR1020227017548A priority patent/KR20220087537A/ko
Priority to IL291807A priority patent/IL291807A/en
Priority to AU2020369581A priority patent/AU2020369581A1/en
Priority to JP2022523875A priority patent/JP2022553377A/ja
Publication of WO2021081277A1 publication Critical patent/WO2021081277A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • sequence listing of the present application is submitted electronically as an ASCII formatted sequence listing with a file name “seqlist10673P2”, creation date of March 20, 2020, and a size of 165 Kb. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety.
  • the present invention relates to methods for administering an antagonist anti-C5 antibody to treat or prevent a C5-related disorder.
  • Paroxysmal nocturnal hemoglobinuria is a chronic, progressive, life- threatening, and rare multisystem disease. Typically, it is characterized by uncontrolled complement activation on red blood cells (RBCs), resulting in intravascular hemolysis (Sahin et al., Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res 2016; 6(2): 19-27), and on white blood cells (WBCs) and platelets, resulting in an increased risk of thrombosis.
  • RBCs red blood cells
  • WBCs white blood cells
  • the estimated incidence of PNH is 1.3 cases per million individuals per year, and the estimated prevalence is 15.9 cases per million individuals per year (Preis & Lowrey, Laboratory tests for paroxysmal nocturnal hemoglobinuria. Am J Hematol 2014; 89(3):339-41).
  • Paroxysmal nocturnal hemoglobinuria is a rare acquired, life-threatening disease of the blood.
  • Defective red blood cells of PNH are extremely susceptible to premature destruction by a particular part of a person’s own immune system called the complement system. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and impaired bone marrow function.
  • CD55-deficient protein-losing enteropathy (CD55-deficient PLE) is a rare disease, also referred to as complement hyperactivation, angiopathic thrombosis, protein-losing enteropathy (CHAPLE disease), that can be treated by C5 blockade (Kurolap et al., Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med., 377(1 ):87-89 (2017); Ozen et al., CD55 Deficiency and Protein-Losing Enteropathy. N Engl J Med.,
  • CD55-deficient PLE/CHAPLE disease is caused by biallelic loss-of-function mutations in the CD55 gene.
  • the absence of CD55 causes overactivation of the complement system, causing the production of various complement products including anaphylatoxins and the membrane-attack complex.
  • CD55-deficient PLE isolated germ line loss of CD55 expression in all tissues manifests in the Gl tract, as primary intestinal lymphangiectasia, which causes PLE.
  • Eculizumab is an antibody directed against C5 which blocks the formation of the MAC - C5b-9, thus protecting PNH RBCs from complement-mediated intravascular hemolysis.
  • C5 MAC - C5b-9
  • PNH RBCs complement-mediated intravascular hemolysis.
  • not all patients receive optimal therapeutic benefit For example, 25% of patients still need recurrent, albeit less frequent, blood transfusions.
  • Up to 20% of patients on eculizumab therapy require significant increases in dose or dose frequency due to breakthrough hemolysis secondary to incomplete inhibition of C5 (Nakayama et al., Eculizumab Dosing Intervals Longer than 17 Days May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.
  • IV administered ravulizumab does not offer the significant convenience and reduced burden of subcutaneous (SC) selfadministration (as originally approved by the US FDA).
  • SC subcutaneous
  • Subcutaneous ravulizumab dosage regimens call for injection of 7 ml in two separate injections over a 10 minute time period.
  • Alexion Investor Day (slide deck), March 20, 2019.
  • the present invention provides methods for administering an antagonist antigenbinding protein that binds specifically to C5 (e.g ., REGN3918) or a pharmaceutical formulation thereof, to a subject suffering from a C5-associated disease (e.g., PNH, aHUS, MG or CHAPLE), comprising introducing, into the body of the subject, one or more doses of about 30 mg/kg of antagonist antigen-binding protein that binds specifically to C5intravenously; and, optionally, one or more doses of the antagonist antigen-binding protein that binds specifically to C5 or a pharmaceutical formulation thereof subcutaneously.
  • a C5-associated disease e.g., PNH, aHUS, MG or CHAPLE
  • the present invention also provides a dosing regimen for administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) to a subject (e.g., a human) comprising introducing, into the body of the subject, (i) one or more doses of about 30 mg/kg of the anti-C5 antigen-binding protein intravenously (IV), then (ii) one or more doses of about 800 mg of the anti-C5 antigen-binding protein, subcutaneously (SC) (e.g., given weekly starting about 7 days after the first dose); or (a) one or more doses of about 30 mg/kg of the anti-C5 antigen-binding protein intravenously (IV), then (b) one or more subcutaneous doses (e.g., given weekly starting about 7 days after the first dose) based on body weight as follows: for body weight (BW) ⁇ 10 kg, 125 mg, for BW >10 kg and ⁇ 20 kg, 200 mg, for BW >20
  • the subcutaneous doses are administered once a week (weekly, q1w or qw).
  • Weekly doses are, in an embodiment of the invention, administered about every 7 days, 7 days (+1 day), 7 days (+2 days) or 7 days (+3 days) after the immediately preceding dose. For example, if an initial dose is given on day 1, then a following weekly dose is given on about day 8 and about every 7 days thereafter.
  • the subject suffers from a C5-associated disease (e.g., PNH, CHAPLE, aHUS or MG).
  • a C5-associated disease e.g., PNH, CHAPLE, aHUS or MG.
  • the present invention further provides a method for treating or preventing CHAPLE disease, in a subject, by administering an antagonist antigen-binding protein that binds specifically to C5 set forth herein, e.g., REGN3918, to a subject, a therapeutically effective amount of the antigen-binding protein.
  • an antagonist antigen-binding protein that binds specifically to C5 set forth herein e.g., REGN3918
  • the present invention also provides a method for treating or preventing a C5- associated disease or reducing C5 complement activity (e.g., by about 99 or 100%, e.g., as measured by CH50 assay, e.g., CH50 assay measuring lysis of sheep red blood cells), in a subject (e.g., a human subject), comprising administering an antagonist antigen-binding protein that binds specifically to C5 ( e.g ., REGN3918), to the subject, by a dosing regimen discussed herein.
  • a C5- associated disease or reducing C5 complement activity e.g., by about 99 or 100%, e.g., as measured by CH50 assay, e.g., CH50 assay measuring lysis of sheep red blood cells
  • a subject e.g., a human subject
  • administering an antagonist antigen-binding protein that binds specifically to C5 e.g ., REGN3918
  • the C5-associated disease is adult respiratory distress syndrome; age-related macular degeneration (AMD); allergy; Alport's syndrome; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); antiphospholipid syndrome (APS); asthma; atherosclerosis; atypical hemolytic uremic syndrome (aHUS); an autoimmune disease; autoimmune hemolytic anemia (AIHA); balloon angioplasty; bronchoconstriction; bullous pemphigoid; burns; C3 glomerulopathy; capillary leak syndrome; a cardiovascular disorder; catastrophic antiphospholipid syndrome (CAPS); a cerebrovascular disorder; CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy); a chemical injury; chronic obstructive pulmonary disease (COPD); cold agglutinin disease (CAD); corneal and/or retinal tissue; Crohn's disease; Degos disease; dense deposit disease (DDD); dermatomyo
  • the present invention also provides a method for establishing and/or maintaining a concentration (e.g . a trough concentration) over time of at least about 100 mg/L, 150 mg/L, 400 mg/L, 600 mg/L, 700 mg/L or 600-700 mg/L of antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) in the serum of a subject (e.g., a human) and/or for achieving at least 80% (e.g., 81, 82, 93, 84, 85, 90, 95% or more) suppression of hemolysis in the serum of a subject (e.g., as measured by AH50 and/or CH50 assay) comprising administering the anti-C5 antigen-binding protein, to the subject, by a dosing regimen as discussed herein.
  • a concentration e.g . a trough concentration
  • the present invention also provides a method for reducing serum lactate dehydrogenase (LDH) levels, intravascular hemolysis and/or the need for transfusions of red blood cells in a subject (e.g., a human) suffering from paroxysmal nocturnal hemoglobinuria (PNH) comprising administering the antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918), to the subject, by a dosing regimen as discussed herein (e.g., (i) one or more doses of about 30 mg/kg of the antigen-binding protein intravenously (IV); then (ii) one or more weekly doses of about 800 mg of the antigenbinding protein, subcutaneously (SC).
  • a dosing regimen as discussed herein (e.g., (i) one or more doses of about 30 mg/kg of the antigen-binding protein intravenously (IV); then (ii) one or more weekly doses of about 800 mg of the antigenbinding protein,
  • a subject e.g., suffering from PNH receiving an antagonist antigen-binding protein that binds specifically to C5 as discussed herein (e.g., REGN3918)
  • LDH serum lactate dehydrogenase
  • the subject has PNH granulocytes (polymorphonuclear [PMN])) of >10%
  • PMN polymorphonuclear
  • the subject has hypoalbuminemia of less than or equal to 3.2 g/dL
  • the subject suffers from diarrhea;
  • the subject suffers from vomiting;
  • the subject suffers from abdominal pain;
  • the subject suffers from peripheral or facial edema;
  • the subject suffers from an episode of infection with concomitant, hypogammaglobulinemia, or a thromboembolic event;
  • the subject suffers from fatigue;
  • the subject suffers from hemoglobin
  • the present invention also provides a method for normalizing and/or increasing serum albumin or reducing therapeutic interventions, in a subject suffering from CD55- deficient protein-losing enteropathy, comprising administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) to the subject by a method according to a dosing regimen set forth herein wherein the therapeutic intervention is one or more selected from the group consisting of: (i) administration of corticosteroids; (ii) administration of immunoglobulin; (iii) administration of albumin; (iv) administration of anti-tumor necrosis factor alpha therapeutic agent; (v) administration of immunomodulator; (vi) administration of micronutrient; (vii) administration of enteral or parenteral supplementation; (viii) administration of anti-coagulant; (ix) administration of antibiotic; and (x) administration of anti-platelet agent.
  • a subject e.g., suffering from CHAPLE
  • an antagonist antigen-binding protein that binds specifically to C5 as discussed herein e.g., REGN3918
  • the subject has a biallelic loss-of-function mutation in CD55;
  • the subject has a biallelic loss-of-function mutation in CD55 which is a frame shift mutation; missense mutation, splice site mutation or nonsense mutation;
  • the subject has hypoalbuminemia of less than or equal to 3.2 g/dL serum albumin;
  • the subject suffers from diarrhea;
  • the subject suffers from vomiting;
  • the subject suffers from abdominal pain;
  • the subject suffers from peripheral or facial edema;
  • the subject suffers from an episode of infection with concomitant hypogammaglobulinemia; and/or (ix) the subject suffers from a thrombotic event.
  • an antagonist antigen-binding protein that binds specifically to C5 as discussed herein is an antibody or antigen-binding fragment thereof such as REGN3918 (pozelimab).
  • an antagonist antigen- binding protein that binds specifically to C5 as discussed herein comprises (1) heavy chain variable region (HCVR) that comprises the amino acid sequence set forth in SEQ ID NO: 2 or HCDR1, HCDR2 and HCDR3 thereof, and a light chain variable region (LCVR) that comprises the amino acid sequence set forth in SEQ ID NO: 10 or LCDR1 , LCDR2 and LCDR3 thereof or LCDR1, LCDR2 and LCDR3 thereof; (2) HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26 or LCDR1, LCDR2 and LCDR
  • HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34 or HCDR1 , HCDR2 and HCDR3 thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42 or LCDR1, LCDR2 and LCDR3 thereof
  • HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58 or LCDR1 , LCDR2 and LCDR3 thereof
  • HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66 or HCDR1, HCDR2 and HCDR3 thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74 or LCDR1 , LCDR2 and LCDR3 thereof
  • HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 or HCDR1 , HCDR2 and HCDR3 thereof, and
  • a subject receiving an antagonist antigen-binding protein that binds specifically to C5 as set forth herein has previously received tesidolumab, eculizumab or ravulizumab.
  • an antagonist antigenbinding protein that binds specifically to C5 as set forth herein is administered in association with a further therapeutic agent; e.g., cemdisiran, an oligonucleotide, anti-coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), an antihypertensive, an angiotensinconverting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, or methotre
  • NSAID non-steroidal anti-
  • the further therapeutic agent is an oligonucleotide which is a DNA oligonucleotide, an RNA oligonucleotide, a single stranded DNA oligonucleotide, a single stranded RNA oligonucleotide, a double stranded DNA oligonucleotide, or a double stranded RNA oligonucleotide; optionally, wherein the oligonucleotide is conjugated to a sugar.
  • the present invention also provides a dosing regimen for administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) to a subject (e.g., a human) comprising introducing, into the body of the subject,
  • an antagonist antigen-binding protein that binds specifically to C5 e.g., REGN3918
  • a subject e.g., a human
  • subcutaneous doses e.g., given weekly starting about 7 days after the first dose
  • body weight as follows: for body weight (BW) ⁇ 10 kg, 125 mg, for BW >10 kg and ⁇ 20 kg, 200 mg, for BW >20 kg and ⁇ 40 kg, 350 mg, for BW > 40 kg and ⁇ 60 kg, 500 mg, and for BW >60 kg, 800 mg.
  • BW body weight
  • the subcutaneous doses are administered once a week (weekly, q1w or qw).
  • Weekly doses are, in an embodiment of the invention, administered about every 7 days, 7 days (+1 day), 7 days (+2 days) or 7 days (+3 days) after the immediately preceding dose. For example, if an initial dose is given on day 1, then a following weekly dose is given on about day 8 and about every 7 days thereafter.
  • the subject suffers from a C5-associated disease (e.g., PNFI, CFIAPLE, aFIUS or MG).
  • PNFI PNFI
  • CFIAPLE CFIAPLE
  • aFIUS aFIUS
  • Methods for treating or preventing a C5-associated disorder comprising said administration methods are within the scope of the present invention.
  • Figure 1 Illustration of cohorts in Study of REGN3918 in Patients with paroxysmal nocturnal hemoglobinuria (PNH).
  • Figure 2 Mean ( ⁇ SE) serum concentrations of total REGN3918 versus nominal time in each treatment group (1 mg/kg IV, single dose; 3 mg/kg IV, single dose; 300 mg SC, single dose; 10 mg/kg IV, single dose; 600 mg SC, single dose; 30 mg/kg IV, single dose; or 15 mg/kg IV followed by 4 repeat SC doses of 400 mg q1w X 4weeks) in healthy human volunteers.
  • Figure 3 Mean ( ⁇ SE) percentage change from baseline in CH50 versus nominal time in each treatment group (1 mg/kg IV, single dose; 3 mg/kg IV, single dose; 300 mg SC, single dose; 10 mg/kg IV, single dose; 600 mg SC, single dose; 30 mg/kg IV, single dose; or 15 mg/kg IV followed by 4 repeat SC doses of 400 mg q1w X 4weeks) in healthy human volunteers.
  • Figure 4 In vitro alternative pathway (AP) and classical pathway (CP) hemolysis in the presence of various concentrations of Dalimab (REGN3918), eculizumab, ravulizumab or isotype control antibody (REGN1945).
  • Figure 4A shows AP hemolysis assay in the presence of 10% normal human serum (NHS).
  • Figure 4B shows AP hemolysis assay in the presence of 25% NHS.
  • Figure 4C shows AP hemolysis assay in the presence of 48% NHS.
  • Figure 4D shows CP hemolysis assays in the presence of 5% NHS.
  • Figure 4E shows CP hemolysis assays in the presence of 10% NHS.
  • Figure 4F shows CP hemolysis assays in the presence of 25% NHS.
  • Figure 4G shows AP hemolysis assay in the presence of 25% NHS and 1 mM MgCh.
  • Figure 4H shows AP hemolysis assay in the presence of 25% NHS and 1.5 mM MgCh.
  • Figure 4I shows AP hemolysis assay in the presence of 25% NHS and 2 mM MgCh.
  • Lactate dehydrogenase (LDH) (X ULN) for six patients (410001001 F; 410001002F; 410004001 F; 410004002M; 410005001 F and 410005002M) over time in normal scale.
  • LDH lactate dehydrogenase
  • X ULN Lactate dehydrogenase
  • Lactate dehydrogenase (LDH) (X ULN), in semi-log scale, for six patients over time.
  • the LDH upper limit of normal (ULN) and 1.5 X ULN is indicated.
  • FIG. 7 Mean lactate dehydrogenase (LDH) (X ULN) for six patients over time in normal scale. The LDH upper limit of normal (ULN) and 1.5 X ULN is indicated.
  • LDH lactate dehydrogenase
  • Figure 8 Mean lactate dehydrogenase (LDH) (X ULN), in semi-log scale, for six patients over time. The LDH upper limit of normal (ULN) and 1.5 X ULN is indicated.
  • Figure 9 (A-D).
  • Figure 9A shows individual, normal scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 9B shows individual, semi-log scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 9C shows median, normal scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 9D shows median, semi-log scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 10 shows individual, normal scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 10B shows individual, semi-log scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 10C shows median, normal scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 10D shows median, semi-log scale concentration of total REGN3918 in serum (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 11 shows individual concentration of total C5 in plasma (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 11B shows median concentration of total C5 in plasma (mg/L) versus nominal time in first 6 PNH na ' ive patients.
  • Figure 12 shows individual concentration of total C5 in plasma (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 12B shows median concentration of total C5 in plasma (mg/L) versus nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 13 shows individual fold over baseline total C5 in plasma by nominal time in first 6 PNH na ' ive patients.
  • Figure 13B shows median fold over baseline total C5 in plasma by nominal time in first 6 PNH na ' ive patients.
  • Figure 14 shows individual fold over baseline total C5 in plasma by nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 14B shows median fold over baseline total C5 in plasma by nominal time in first 6 PNH na ' ive patients, by gender.
  • Figure 15 Mean ( ⁇ SD) concentration (mg/L) of total C5 in plasma versus nominal time in first 6 PNH na ' ive patients.
  • FIG. 16 Collection of graphs showing individual concentrations, in six patients (A, B, C, D, E, and F), of total REGN3918 (TOR3918; triangles) and total C5 (TOC5; circles) versus nominal time.
  • Figure 24 Semi-log scale mean LDH (X ULN) for 9 patients beyond day 57.
  • Figure 25 Summary of study of treatment of na ' ive PNH patients with ALXN1210 (ravulizumab) or eculizumab.
  • Figure 26 (A-D). Dose switching from eculizumab to REGN3918 results in normalization of serum C5 concentrations and maintained suppression of hemolytic activity.
  • Figure 26A shows total hlgG concentration was measured by Gyros in serum collected from C5hu/hu mice administered 3 doses of REGN3918 alone (closed circles), 3 doses of eculizumab alone (squares), or 1 dose of eculizumab followed by 2 doses of REGN3918 (switch, open circles). Arrowheads on y-axis and vertical grey dashed lines indicate times of dosing.
  • Figure 26B shows total C5 serum concentrations in C5hu/hu mice administered REGN3918 alone (closed circles), eculizumab alone (squares), or switched from eculizumab to REGN3918 (switch, open circles) were measured from mice bled over the duration of the study.
  • Figure 26C shows serum collected from terminally bled C5hu/hu mice administered with REGN3918 alone (closed circles), eculizumab alone (squares), or eculizumab/REGN3918 switched (open circles) were supplemented with hC3 and the percent of CP-mediated hemolysis using ex vivo assays was assessed.
  • Figure 26D shows serum concentrations of total C5 and hlgG were used to calculate the ratio of C5:mAb at the indicated times. Data is plotted as mean ⁇ SEM.
  • Figure 27 REGN3918 and eculizumab bind to distinct sites on C5 and when all three are present under conditions that are designed to mimic dose switching, form complexes predominantly containing 1 to 2 molecules of C5. Eculizumab:C5 complexes were analyzed by asymmetric flow field-flow fractionation coupled to multi-angle laser light scattering (A4F-MALLS). Fractograms from individual samples of eculizumab, C5, and REGN3918 are also overlaid. Relative UV absorbance at 215 nm as a function of retention time is shown for each sample and the measured molar masses of resolved peaks are indicated.
  • Figure 28A shows serum albumin levels of the four CHAPLE patients during the treatment period.
  • Figure 28B shows serum albumin levels of a first of the four CHAPLE patients before treatment.
  • Figure 28C shows serum albumin levels of a second of the four CHAPLE patients before treatment.
  • Figure 28D shows serum albumin levels of a third of the four CHAPLE patients before treatment.
  • Figure 28E shows serum albumin levels of a fourth of the four CHAPLE patients before treatment.
  • the lower level of normal (LLN) for the male and female patients is indicated.
  • FIG. 29 Plot of total serum protein in four individual CHAPLE patients over time starting at baseline. The lower level of normal (LLN) and upper level of normal (ULN) are indicated.
  • Figure 30 Plot of vitamin B12 levels over time in four individual CHAPLE patients during the treatment period from baseline.
  • Figure 31 Plot of platelet counts over time in four individual CHAPLE patients during the treatment period from baseline.
  • Figure 32 Plot of fecal alpha-1 -antitrypsin concentration over time in four individual CHAPLE patients during the treatment period from baseline. The upper level of normal (ULN) is indicated.
  • Figure 33 Plot of facial edema grade in four individual CHAPLE patients over time before and during the treatment period.
  • Figure 34 Plot of peripheral edema grade in four individual CHAPLE patients over time before and during the treatment period.
  • Figure 35 Plot of the daily average of bowel movements per week for four individual CHAPLE patients. DETAILED DESCRIPTION OF THE INVENTION
  • REGN3918 (pozelimab) dosing regimen including a subcutaneous dosing component, for treating C5-related disorders, such as PNH, in humans has been developed.
  • Subcutaneous dosing gives patients the option for home-dosing and, thus, offers the advantage of greater patient compliance over the IV dosing regimens of eculizumab and ravulizumab.
  • This dosing regimen has been shown to be highly effective for controlling hemolysis and reducing breakthrough hemolysis in human patients receiving the antibody.
  • REGN3918 administered 30 mg/kg IV followed by 800 mg once weekly SC demonstrated robust inhibition of intravascular hemolysis, with normalization of LDH in human patients with PNH.
  • REGN3918 is known to bind with high affinity to C5 (R885H/C), it has been shown, in human PNH patients receiving the REGN3918-30 + 800 dosing regimen, to effectively normalize LDH. Data presented herein demonstrated REGN3918-30 + 800 dosing regimen efficacy in a human patient with the C5 variant that was resistant to prior eculizumab therapy. The REGN3918-30 + 800 dosing regimen also exhibited clinical advantages over eculizumab and ravulizumab.
  • the present invention provides methods for using antagonist antigen-binding proteins that bind specifically to C5 (e.g., antibodies and antigen-binding fragments thereof) and pharmaceutical formulations thereof comprising a pharmaceutically acceptable carrier, as specified herein.
  • C5 e.g., antibodies and antigen-binding fragments thereof
  • pharmaceutical formulations thereof comprising a pharmaceutically acceptable carrier, as specified herein.
  • the antagonist antigen-binding protein that binds specifically to C5 binds to the beta chain or the alpha chain of C5 or both, e.g., at residues 591-599 and/or 775-794, e.g., (SEQ ID NO: 353) and/or (SEQ ID NO: 354).
  • the anti-C5 antigen-binding protein does not bind C5a.
  • the antagonist antigen-binding protein that binds specifically to C5 binds at residues (SEQ ID NO: 355).
  • the antagonist antigen-binding protein that binds specifically to C5 binds the beta chain of C5 thereof, e.g. at residues 332-398, 332-378, 332-364, 332-348, 350-420, 369-409, 379-398 and/or 386-392.
  • the antagonist antigen-binding protein that binds specifically to C5 binds C5a, e.g. at residues (SEQ ID NO: 356) and/or (SEQ ID NO: 357).
  • the antagonist antigen-binding protein that binds specifically to C5 binds the beta chain of C5, e.g., residues 19-180.
  • binding to C5 is reduced by E48A, D51A and/or K109A C5 mutations.
  • Immunoglobulin polypeptides in antagonist antigen-binding protein that binds specifically to C5 e.g., antibody or antigen-binding fragment thereof
  • C5 e.g., antibody or antigen-binding fragment thereof
  • Antibodies and fragments may include one or more variants of said sequences See WO2017/218515 Polynucleotides encoding the chains set forth in Table A are set forth below in Table B.
  • Antibodies and fragments may include one or more variants of said sequences See WO2017/218515
  • any antigen-binding protein that binds specifically to C5 (anti-C5) which is discussed herein is an antagonist.
  • an antagonist e.g ., an antagonist antigen-binding protein that binds specifically to C5
  • binds to C5 and inhibits at least one biological activity of C5 for example, preventing or blocking complement- mediated hemolysis by classical pathway or alternative pathway and/or inhibits cleavage of C5 to C5a and C5b and/or inhibits complement mediated lysis of red blood cells and/or inhibits formation of membrane attack complex (MAC) and/or inhibits formation of C5b-6 complex.
  • MAC membrane attack complex
  • the antagonist antigen-binding protein that binds specifically to C5 is eculizumab (sold as Soliris), ravulizumab (ALXN1210; sold as Ultomihs), tesidolumab (see US8241628; WO 2010/015608; or WO2017/212375) or mubodina (see US7999081); or an antigen-binding fragment thereof.
  • the antagonist antigen-binding protein that binds specifically to C5 is Pozelimab (REGN3918; H4H12166P) antibody comprises a heavy chain immunoglobulin comprising the amino acid sequence:
  • the present invention includes methods for using antagonist antigen-binding proteins that bind specifically to C5, e.g., antibodies and antigen-binding fragments thereof, that include the variable regions (VH and VL) and/or CDRs (VL with LCDR1 , LCDR2 and LCDR3; and VH with HCDR1 , HCDR2 and HCDR3) which are specifically discussed herein (e.g., of Pozelimab) as well as variable regions and CDRs which are variants of those discussed herein.
  • VH and VL variable regions
  • CDRs VL with LCDR1 , LCDR2 and LCDR3
  • VH with HCDR1 , HCDR2 and HCDR3 VH with HCDR1 , HCDR2 and HCDR3
  • a “variant" of a polypeptide refers to a polypeptide comprising an amino acid sequence that is at least about 70-99.9% (e.g ., at least 70, 72, 74, 75, 76, 79,
  • a variant of a polypeptide may include a polypeptide such as an immunoglobulin chain specifically set forth herein (e.g., the ravulizumab, eculizumab, tesidolumab or mubodina VH, VL, HC or LC or CDR thereof); but including one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations, e.g., one or more missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions.
  • an immunoglobulin chain specifically set forth herein e.g., the ravulizumab, eculizumab, tesidolumab or mubodina VH, VL, HC or LC or CDR thereof
  • one or more mutations e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • missense mutations e.g., conservative substitutions
  • the present invention includes methods for using antagonist antigen-binding proteins that bind specifically to C5, e.g., antibodies and antigen-binding fragments thereof, which include an immunoglobulin light chain (or VL) variant comprising the amino acid sequence set forth in SEQ ID NO: 106 but having one or more of such mutations and/or an immunoglobulin heavy chain (or VH) variant comprising the amino acid sequence set forth in SEQ ID NO: 98 but having one or more of such mutations.
  • an immunoglobulin light chain (or VL) variant comprising the amino acid sequence set forth in SEQ ID NO: 106 but having one or more of such mutations
  • an immunoglobulin heavy chain (or VH) variant comprising the amino acid sequence set forth in SEQ ID NO: 98 but having one or more of such mutations.
  • the antagonist antigen-binding protein that binds specifically to C5 includes an immunoglobulin light chain variant comprising CDR-L1 , CDR-L2 and CDR-L3 wherein one or more ( e.g ., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions) and/or an immunoglobulin heavy chain variant comprising CDR-H1 , CDR-H2 and CDR-H3 wherein one or more (e.g., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions).
  • an immunoglobulin light chain variant comprising CDR-L1 , CDR-L2 and CDR-L3 wherein one or more (e.g ., 1 or 2 or 3) of such CDRs has one or more of such mutations (e.g., conservative substitutions).
  • BLAST ALGORITHMS Altschul et ai. (2005) FEBS J. 272(20): 5101-5109; Altschul, S. F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et ai, (1993) Nature Genet. 3:266-272; Madden, T. L., et ai, (1996) Meth. Enzymol. 266:131-141; Altschul, S. F., et ai, (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et ai, (1997) Genome Res.
  • antagonist antigen-binding proteins that bind specifically to C5, e.g., antibodies and antigen-binding fragments thereof (including multi-specific antigen-binding proteins), that bind specifically to C5 (e.g., human C5), comprising an immunoglobulin heavy chain or variable region thereof (VH) comprising the amino acid sequence specifically set forth herein corresponding, in Table A, to (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 138; 146; 122; 146; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322 or 338) (or a variant thereof), and/or an immunoglobulin light chain or variable region thereof (VL) comprising the amino acid sequence specifically set forth herein corresponding, in Table A, to (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 130
  • the VH is linked to a constant heavy chain domain, such as a human constant heavy chain domain (e.g., IgG, IgG 1 or lgG4 (e.g., lgG4 (S228P mutant, Eu numbering))) and/or the VL is linked to a constant light chain domain, such as a human constant light chain domain (e.g., lambda or kappa).
  • a human constant heavy chain domain e.g., IgG, IgG 1 or lgG4 (e.g., lgG4 (S228P mutant, Eu numbering)
  • the VL is linked to a constant light chain domain, such as a human constant light chain domain (e.g., lambda or kappa).
  • the heavy chain constant domain is lgG4 having he S108P mutation.
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11683N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 ( e.g ., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11686N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12159P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12161P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12163P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12164P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P2 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 ( e.g ., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P3, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P4 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P5 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P6, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P7 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P8, comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114 ( e.g ., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P9 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12166P10 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12167P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12168P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12169P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12170P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12171P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226 ( e.g ., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12175P comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12176P2 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12177P2 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H4H12183P2 comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11682N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11684N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314 ( e.g ., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11694N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the antagonist antigen-binding protein that binds specifically to C5, H2M11695N comprises an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338 and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346 (e.g., wherein the antigen-binding protein is an antibody or antigen-binding fragment thereof).
  • the present invention includes antigen-binding proteins comprising the VH and V L variable domains set forth herein (e.g., ravulizumab, eculizumab, tesidolumab or mubodina) which are linked to a heavy and/or light chain constant domain, respectively, e.g., as set forth above (e.g., a VH linked to a human lgG4 heavy chain constant region and a VL linked to a human kappa light chain constant region).
  • VH and V L variable domains set forth herein e.g., ravulizumab, eculizumab, tesidolumab or mubodina
  • a heavy and/or light chain constant domain e.g., as set forth above (e.g., a VH linked to a human lgG4 heavy chain constant region and a VL linked to a human kappa light chain constant region).
  • antibody refers to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (HCs) including three H-CDRs and two light chains (LCs) including three L-CDRs, inter-connected by disulfide bonds (e.g. lgG4)-for example
  • HCs heavy chains
  • LCs light chains
  • disulfide bonds e.g. lgG4
  • the assignment of amino acids to each CDR domain within an immunoglobulin chain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et a!.-, National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem.
  • the present invention includes antibodies and antigen-binding fragments including the CDRs of a VH and the CDRs of a VL , which VH and VL comprise amino acid sequences as set forth herein (or a variant thereof), wherein the CDRs are as defined according to Kabat and/or Chothia.
  • antigen-binding portion or “antigen-binding fragment” of an antibody or antigen-binding protein, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that does not include all sequences of an antibody, but which specifically binds an antigen (e.g., C5).
  • an antigen e.g., C5
  • Non-limiting examples of antigen-binding fragments include: (i) F(ab) and F(ab’) fragments; (ii) F(ab') 2 fragments; (iii) Fd fragments (heavy chain portion of a Fab fragment cleaved with papain); (iv) Fv fragments (a VH or VL); and (v) single-chain Fv (scFv) molecules; having the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • the antigen-binding fragment comprises three or more CDRs of (e.g., CDR-H1 , CDR-H2 and CDR-H3; and/or CDR-L1, CDR- L2 and CDR-L3).
  • recombinant antigen-binding proteins refers to such molecules created, expressed, isolated or obtained by technologies or methods known in the art as recombinant DNA technology which include, e.g., DNA splicing and transgenic expression.
  • the term includes antibodies expressed in a non-human mammal (including transgenic non-human mammals, e.g., transgenic mice), or a host cell (e.g., Chinese hamster ovary (CFIO) cell) or cellular expression system or isolated from a recombinant combinatorial human antibody library.
  • CFIO Chinese hamster ovary
  • the present invention includes methods for using recombinant antigen-binding proteins as set forth herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161 P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171 P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N).
  • H2M11683N
  • the present invention includes methods for using monoclonal antagonist antigenbinding proteins that bind specifically to C5 (e.g., antibodies and antigen-binding fragments thereof).
  • monoclonal antibody or “mAb”, as used herein, refers to an antibody from a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts.
  • the modifier "monoclonal” is not to be construed as requiring production of the antibody by any particular method.
  • Monoclonal antibodies may be made by the hybridoma method of Kohler et at. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • Isolated antagonist antigen-binding proteins that bind specifically to C5 (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the system, cells or cell culture from which they are produced.
  • biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as cellular debris and growth medium.
  • An isolated antigen-binding protein may be at least partially free of the growth medium in which a host cell expressing the antigen-binding protein is grown.
  • isolated is not intended to be limited to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies or antigen-binding fragments).
  • antigen-binding proteins e.g., antibodies or antigen-binding fragments
  • an “anti-C5” antigen-binding protein specifically binds to C5 (e.g., human C5 or cynomolgous monkey C5).
  • the term “specifically binds” refers to those antigen-binding proteins (e.g., mAbs) having a binding affinity to an antigen at 25°C, expressed as KD, of at least about 10 9 M or less (a lower number) (e.g., about 10 10 M, about 10 11 M or about 10 12 M), as measured by real-time, label free bio-layer interferometry assay, e.g., an Octet® HTX biosensor, or by surface plasmon resonance, e.g., BIACORETM, or by solution-affinity ELISA.
  • mAbs those antigen-binding proteins having a binding affinity to an antigen at 25°C, expressed as KD, of at least about 10 9 M or less (a lower number) (e.g., about 10 10 M, about 10 11
  • the KD for binding to human C5 is about 189 pM; for binding to human C5 (R885C or R885H) is about 400-500 pM; and for binding to cynomolgus monkey C5 is about 2-3 nM at 25°C, pH7.4, by surface plasmon resonance assay.
  • human C5 (including the signal sequence) comprises the amino acid sequence set forth in SEQ ID NO: 362; and mature human C5 comprising the mutation R885H comprises the amino acid sequence set forth in SEQ ID NO: 363.
  • the present invention includes methods for the treatment or prevention of a C5- associated disease and/or for ameliorating at least one sign or symptom associated with such C5-associated disease, in a subject, by administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) to the subject as follows:
  • SC dose(s) may be given on a weekly basis following the initial IV dose(s).
  • the weekly doses can be continued indefinitely, for example, as long as a therapeutic effect or prevention of an undesired outcome (e.g., loss of serum albumin, or increase in serum LDH levels) is desired.
  • an undesired outcome e.g., loss of serum albumin, or increase in serum LDH levels
  • the subject is administered one or more doses of an oligonucleotide (e.g., cemdisiran) in association with the antigen-binding protein.
  • the antagonist antigen-binding protein that binds specifically to C5 is administered to a patient in a method as set forth herein (e.g., for treating or preventing PNH or CHAPLE) with the proviso that no other agent which reduces complement activity (e.g., that reduces C5 activity), for example, an oligonucleotide (e.g., that reduces C5 expression) such as cemdisiran, or an antibody or antigen-binding fragment thereof that binds specifically to C5, is administered to the patient.
  • a method as set forth herein e.g., for treating or preventing PNH or CHAPLE
  • an oligonucleotide e.g., that reduces C5 expression
  • cemdisiran an antibody or antigen-binding fragment thereof that binds specifically to C5
  • the present invention also includes methods for treating or preventing a C5- associated disease (e.g ., PNH or CHAPLE) by administering one or more doses (e.g ., one or more than one) of about 30 mg/kg (body weight (BW)) of the antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918) or pharmaceutical formulation thereof, intravenously (IV).
  • a C5-associated disease e.g ., PNH or CHAPLE
  • one or more doses e.g ., one or more than one
  • BW body weight
  • IV intravenously
  • An intravenous dose of 30 mg/kg has been demonstrated to help to quickly achieve the steady-state trough concentrations of the antigen-binding protein (e.g., antibody) required for sustained maximal CH50 inhibition which, thus, would lead to a therapeutic effect in the subject.
  • further subcutaneous doses of antigen-binding protein may be given to the subject, e.g., weekly
  • the subject e.g., who suffers from PNH
  • SC subcutaneously
  • the present invention includes a method for treating or preventing CHAPLE disease in a subject comprising administering, to the subject, a therapeutically effective dose of antagonist antigen-binding protein that binds specifically to C5 selected from H2M11683N; H2M11686N; H4H12159P; H4H12161 P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4HI2168P; H4HI2169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N;
  • Dosing once a week or weekly dosing or QW dosing refers to administering one or more doses where each occurs about 7 ( e.g ., +1 , +2 or +3) days after the immediately preceding dose.
  • the IV and first SC dose are given on the same day.
  • the antagonist antigen-binding protein that binds specifically to C5, when administered subcutaneously (SC), is delivered in less than 7 ml volume, about 0.625 ml, about 1 ml, about 1.75 ml, about 2.5 ml, about 4 ml, about 0.5-4.0 ml, or about 0.625-4.0 ml.
  • each SC dose is delivered in a single injection.
  • the SC injection is delivered in about 60 seconds or less.
  • a subject e.g., who suffers from a C5-associated disease
  • one or more doses of an antagonist antigen-binding protein that binds specifically to C5 as follows: 1 mg/kg IV; 3 mg/kg IV; 300 mg SC; 800 mg SC; 10 mg/kg IV; 600 mg SC; or 30 mg/kg IV; or, a loading dose of 15 mg/kg IV followed by one or more SC doses of 400 mg administered once weekly.
  • C5 activity e.g., alternative, classical and lectin pathways
  • the present invention includes methods for suppressing complement activity or C5 activity (e.g., alternative pathway (AP)) (e.g., suppressing C5 activity to about its maximal level (e.g., at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%); e.g., which is measured as AH50 and/or CH50 activity) in a subject comprising administering one or more doses of the antigen-binding protein at sufficient levels so as to maintain the serum concentration of the anti-C5 antigen-binding protein at about 100 mg/liter or more (e.g., 150, 400, 600 or 700 mg/liter).
  • the dosing regimen comprises
  • administering one or more doses e.g., 1 dose of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally,
  • administering one or more weekly doses e.g., 2 or more of about 800 mg of the antigen-binding protein (e.g., subcutaneously (SC)); or, one or more weekly doses, administered subcutaneously (SC) depending on body weight (BW), as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; or for BW >60 kg: about 800 mg.
  • the weekly doses can be continued indefinitely, for example, as long as maintenance of the serum concentration of the anti-C5 antigenbinding protein and/or suppression of the C5 activity is desired.
  • the present invention includes methods for achieving or achieving and maintaining a serum concentration (e.g., a steady state serum trough concentration over time) of about 100 mg/liter or more antagonist antigen-binding protein that binds specifically to C5 in a subject comprising: (i) administering one or more doses (e.g., 1 dose) of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally,
  • administering one or more weekly doses e.g., 2 or more of about 800 mg of the antigen-binding protein (e.g., subcutaneously (SC)); or one or more weekly doses, administered subcutaneously (SC) depending on body weight (BW) as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; or for BW >60 kg: about 800 mg.
  • the weekly doses can be continued indefinitely, for example, as long as maintenance of the anti-C5 antigen-binding protein serum concentration is desired.
  • the present invention further provides methods for switching a subject from a therapeutic regimen that includes administration of eculizumab or ravulizumab to a therapeutic regimen that includes administration of an antagonist antigen-binding protein that binds specifically to C5 selected from: comprising administering an initial dose of the antigenbinding protein to the subject when the next dose is due in the eculizumab or ravulizumab therapeutic regimen and ceasing further administrations of the eculizumab or ravulizumab.
  • the initial dose of the antigen-binding protein is about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV), which is optionally followed by one or more further IV doses.
  • the subject is administered one or more weekly subcutaneous doses (e.g ., 2 or more) of about 800 mg of the antigen-binding protein; or one or more weekly subcutaneous doses depending on body weight (BW) as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; or for BW >60 kg: about 800 mg.
  • such a switching method excludes overlapping the eculizumab or ravulizumab dosing regimens with the dosing regimen of the antagonist anti
  • the intravenous infusion of the antagonist antigen-binding protein that binds specifically to C5 is interrupted and restarted at 50% of the original infusion rate if, during the infusion, the subject suffers from one or more adverse events, such as, for example: cough, rigors/chills, Rash, pruritus (itching), urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), vomiting or flushing.
  • adverse events such as, for example: cough, rigors/chills, Rash, pruritus (itching), urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), vomiting or flushing.
  • C5-associated disease refers to a disease, disorder, condition or syndrome which is caused, maintained or exacerbated, or whose signs and/or symptoms are caused, maintained or exacerbated, directly or indirectly, by complement system activity wherein the complement system activity can be reduced or stabilized or eliminated by inhibition of C5 activity.
  • Such C5 activity can be inhibited by preventing, for example, cleavage of C5 precursor into C5a and C5b chains, formation of membrane attack complex (MAC) and/or binding of the MAC to the surface of a target cell (e.g., a red blood cell).
  • MAC membrane attack complex
  • C5 activity inhibition is as measured in a CH50 assay.
  • CH50 50% Hemolytic Complement
  • CH50 is an assay to determine the level of classical complement pathway and it is sensitive to the reduction, absence and/or inactivity of any component of the pathway which is well known in the art.
  • CH50 tests the functional capability of serum complement components of the classical pathway to lyse, for example, sheep red blood cells (SRBC) pre-coated with rabbit anti-sheep red blood cell antibody (haemolysin).
  • SRBC sheep red blood cells
  • haemolysin rabbit anti-sheep red blood cell antibody
  • the classical pathway of complement is activated and hemolysis results. If a complement component is absent, the CH50 level will be zero; if one or more components of the classical pathway are decreased, the CH50 will be decreased.
  • a fixed volume of optimally sensitized SRBC is added to each serum dilution. For example, after incubation, the mixture is centrifuged and the degree of hemolysis is quantified by measuring the absorbance of the hemoglobin released into the supernatant at 540 nm. The amount of complement activity is determined by examining the capacity of various dilutions of test serum to lyse antibody coated SRBC. See Costabile, Measuring the 50% haemolytic complement (CH50) activity of serum, J Vis Exp. 2010 (37): 1923; and Mayer, Complement and complement fixation, 1 p. 133-240. In E. A. 2 Kabat and M. M. Mayer (ed.), Experimental immunochemistry. Thomas, Springfield. AH50 is an analogous test to measure alternate-pathway function.
  • CH50 haemolytic complement
  • Detection of low or absent hemolytic activity in CH50 and/or AH50 directs further complement analysis. See e.g., Joiner et at., 1983. A study of optimal reaction conditions for an assay of the human alternative complement pathway. Am. J. Clin. Pathol. 79:65-72.
  • a therapeutically effective amount of antagonist antigen-binding protein that binds specifically to C5 is an amount that reverses, stabilizes or eliminates an undesired disease or disorder (e.g., a C5-associated disease), for example, by causing the regression, stabilization or elimination of one or more signs or symptoms of such disease or disorder by any clinically measurable degree, e.g., with regard to C5-associated disease, by causing a reduction in or maintenance of complement activity.
  • the dosage regimens set forth herein are examples of therapeutically effective amounts of the antagonist antigen-binding proteins.
  • treat refers to a therapeutic measure that reverses, stabilizes or eliminates an undesired disease or disorder (e.g., a C5-associated disease such as PNH, MG, aHUS or CHAPLE), for example, by causing the regression, stabilization or elimination of one or more signs or symptoms of such disease or disorder by any clinically measurable degree, e.g., with regard to C5-associated disease, by causing a reduction in or maintenance of complement activity.
  • a C5-associated disease e.g., a C5-associated disease such as PNH, MG, aHUS or CHAPLE
  • Subjective evidence of a disease, disorder, condition or syndrome is a symptom.
  • a sign is objective evidence of the disease, disorder, condition or syndrome. For example, blood coming out a nostril is a sign insofar as it is apparent to the patient, physician, and others. Anxiety, low back pain, and fatigue are symptoms insofar as only the patient can perceive them.
  • subject refers to a mammal such as a human, mouse, goat, rabbit, rat, dog, non-human primate or monkey.
  • amino acid Arginine 885 is mutated in the subject’s C5 (e.g. human C5) to another amino acid, e.g., R885H or R885C.
  • a subject has previously received an antagonist antigen-binding protein that binds specifically to C5 other than what is currently being administered, e.g., wherein the subject previously received ravulizumab or eculizumab.
  • a C5-associated disease is, for example: adult respiratory distress syndrome age-related macular degeneration (AMD) allergy
  • ALS Amyotrophic lateral sclerosis
  • APS antiphospholipid syndrome
  • asthma atherosclerosis atypical hemolytic uremic syndrome (aHUS) an autoimmune disease autoimmune hemolytic anemia (AIHA) balloon angioplasty bronchoconstriction bullous pemphigoid burns
  • C3 glomerulopathy capillary leak syndrome a cardiovascular disorder catastrophic antiphospholipid syndrome (CAPS) a cerebrovascular disorder • CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy) a chemical injury chronic obstructive pulmonary disease (COPD) cold agglutinin disease (CAD) corneal and/or retinal tissue
  • Degos disease dense deposit disease DDD
  • DME dermatomyositis diabetes diabetic angiopathy diabetic macular edema
  • DME diabetic nephropathy diabetic retinopathy dilated cardiomyopathy disorder of inappropriate or undesirable complement activation dyspnea eclampsia emphysema epidermolysis bullosa epilepsy fibrogenic dust disease frostbite geographic atrophy (GA) glomerulonephritis glomerulopathy Goodpasture's Syndrome Graves' disease Guillain-Barre Syndrome Hashimoto's thyroiditis hemodialysis complications hemolysis-elevated liver enzymes-and low platelets (HELLP) syndrome hemolytic anemia hemoptysis
  • IgA nephropathy an immune complex disorder immune complex vasculitis immune complex-associated inflammation an infectious disease inflammation caused by an autoimmune disease an inflammatory disorder inherited CD59 deficiency injury due to inert dusts and/or minerals interleukin-2 induced toxicity during IL-2 therapy ischemia-reperfusion injury
  • Kawasaki's disease a lung disease or disorder lupus nephritis membrane proliferative glomerulonephritis membranoproliferative nephritis mesenteric artery reperfusion after aortic reconstruction mesenteric/enteric vascular disorder multifocal motor neuropathy (MMN) multiple sclerosis myasthenia gravis myocardial infarction myocarditis neurological disorder neuromyelitis optica obesity ocular angiogenesis ocular neovascularization affecting choroidal organic dust disease parasitic disease Parkinson's disease paroxysmal nocturnal hemoglobinuria (PNH), e.g., active PNH pauci-immune vasculitis pemphigus percutaneous transluminal coronary angioplasty (PTCA) peripheral (e.g., musculoskeletal) vascular disorder pneumonia post-ischemic reperfusion condition post-pump syndrome in cardiopulmonary bypass post-pump syndrome in renal bypass pre-eclampsi
  • the present invention includes methods for treating or preventing a C5-associated disease (e.g ., PNH or aHUS), in a subject ( e.g ., a human) in need thereof e.g., in a subject suffering from the C5-associated disease, comprising administering an antagonist antigenbinding protein that binds specifically to C5 (e.g., ravulizumab or eculizumab) to the subject according to a dosing regimen set forth herein, optionally in association with a further therapeutic agent (e.g., cemdisiran).
  • the present invention provides methods for reducing the need for therapeutic interventions needed to address various signs and symptoms of C5-associated diseases such as PNH or CHAPLE.
  • Paroxysmal nocturnal hemoglobinuria originates from a multipotent, hematopoietic stem cell (HSC) that acquires a mutation of the phosphatidylinositol glycan anchor biosynthesis class A (PIGA ) gene.
  • HSC hematopoietic stem cell
  • PIGA phosphatidylinositol glycan anchor biosynthesis class A
  • the PIGA gene product is required for the biosynthesis of the glycophosphatidylinositol (GPI) anchor, a glycolipid moiety that attaches dozens of proteins to the plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a reduction or absence of GPI-anchored proteins.
  • the mature blood cells derived from the hematopoietic clone can have a complete deficiency (type III) or a partial deficiency (type II) of GPI-linked proteins (Hillmen et al., Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350(6):552-9).
  • Two of the proteins that are affected by the absence of GPI anchors are CD55 and CD59, complement regulatory proteins.
  • CD55 regulates complement activation by inhibiting complement component 3 (C3) convertases
  • CD59 inhibits the assembly of the membrane-attack complex (MAC) C5b-C9 by interacting with C8 and C9
  • MAC membrane-attack complex
  • Complications of PNH include thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension (Hillmen et al., The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355(12): 1233-43).
  • Thromboembolism is a common cause of mortality in patients with PNH.
  • Potential mechanisms for thromboembolism include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other GPI-linked proteins, and endothelial dysfunction (Hill et al., Thrombosis in paroxysmal nocturnal hemoglobinuria.
  • the present invention includes methods for reducing the need for blood transfusions to address anemia secondary to hemolysis that is caused by PNH, reducing the need for erythropoietin, iron supplements and/or folic acid, reducing the incidence of anemia, reducing the incidence of hemoglobinuria or reducing the incidence of hemolysis, in a subject suffering from PNH, by administering, to the subject, an antagonist antigen- binding protein that binds specifically to C5 such as REGN3918 by a dosing regimen set forth herein.
  • the diagnosis of PNH can be established using an internationally accepted definition of presence of PNH granulocyte clone size of >10% measured in peripheral blood by flow cytometry.
  • An accepted definition of “active disease” is the presence of 1 or more of the following PNH-related signs or symptoms within 3 months: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin ⁇ 10 g/dL), history of a major adverse vascular event (MAVE; including thrombosis), dysphagia, or erectile dysfunction.
  • activity can be established by a history of RBC transfusion due to PNH within 3 months. Methods for treating active PNH are also included within the scope of the present invention.
  • CHAPLE disease CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy
  • CD55 also known as decay accelerating factor, DAF
  • Signs and symptoms of CHAPLE can include hypoproteinemia (low serum levels of albumin and immunoglobulins)-hypoproteinemia leads to facial and extremity edema and recurrent infections, malabsorption syndrome (chronic diarrhea, failure to thrive, anemia, and micronutrient deficiencies), complement overactivation, intestinal lymphangiectasia (IL) and bowel inflammation; and/or increased susceptibility to visceral thrombosis.
  • hypoproteinemia low serum levels of albumin and immunoglobulins
  • malabsorption syndrome chronic diarrhea, failure to thrive, anemia, and micronutrient deficiencies
  • IL intestinal lymphangiectasia
  • bowel inflammation and/or increased susceptibility to visceral thrombosis.
  • CHAPLE disease is caused by biallelic loss-of-function mutations in the CD55 gene. Clinically, it manifests as a familial form of protein-losing enteropathy (PLE) caused by primary intestinal lymphangiectasia (PI L) or Waldmann’s disease that is frequently severe and can be accompanied by lethal systemic manifestations.
  • PLE protein-losing enteropathy
  • PI L primary intestinal lymphangiectasia
  • Waldmann Waldmann’s disease that is frequently severe and can be accompanied by lethal systemic manifestations.
  • CD55 is a glycophosphatidylinositol (GPI)- anchored membrane protein that inhibits the enzymatic activity of C3b and C4b, thus preventing the formation of C3 and C5 convertases that lead ultimately to the assembly of the membrane-attack complex (C5b-C9).
  • GPI glycophosphatidylinositol
  • CD55 loss is specific to hematopoietic cells (CD59 is another GPI-linked complement regulatory protein).
  • CD59 is another GPI-linked complement regulatory protein.
  • the resultant complement- mediated lysis of red cells and platelets gives rise to intravascular hemolysis and thrombosis in PNH.
  • CHAPLE isolated germ line loss of CD55 expression in all tissues manifests in the Gl tract, as primary intestinal lymphangiectasia, which causes PLE.
  • the present invention includes methods for reducing the need for the administration of corticosteroids, immunoglobulin, albumin, biological therapeutic agents (e.g., antibodies or antigen-binding fragments thereof such as anti-TNFalpha, or vedolizumab), immunomodulators (e.g., azathioprine or mesalazine), micronutrients, enteral or parenteral supplementation, anticoagulants (e.g., low-molecular-weight heparin), antibiotics and/or anti-platelet agents (e.g., aspirin, such as low-dose aspirin), in a subject suffering from CHAPLE, by administering, to the subject, an antagonist antigen-binding protein that binds specifically to C5, such as REGN3918, by a dosing regimen set forth herein.
  • biological therapeutic agents e.g., antibodies or antigen-binding fragments thereof such as anti-TNFalpha, or vedolizumab
  • immunomodulators e.g.,
  • CD55 mutations associated with CHAPLE disease include, for example,
  • human CD55 comprises the amino acid sequence set forth in SEQ ID NO: 364; human CD55 comprising the mutation Glu50Alafs*12 comprises the amino acid sequence set forth in SEQ ID NO: 365 (residues 101-200); human CD55 comprising the mutation Gly37Alafs*24 comprises the amino acid sequence set forth in SEQ ID NO: 366 (residues 1-100); and human CD55 comprising the mutation Cys267Ser comprises the amino acid sequence set forth in SEQ ID NO: 367 (residues 201-300) (see International patent application publication no. WO2018/053039).
  • Diagnosis of CHAPLE can be done by genetic analysis to identify a CD55 loss-of- function mutation. Diagnosis can be confirmed by flow cytometry or Western blotting of peripheral blood cells to identify decreased presence of CD55.
  • Active CHAPLE disease is, in an embodiment of the invention, characterized by hypoalbuminemia of less than or equal to 3.2 g/dL, and one or more of the following signs or symptoms which are attributable to CHAPLE: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection with concomitant hypogammaglobulinemia, or a new thromboembolic event.
  • the normal range of serum albumin is typically about 3.5-5.5 g/dL.
  • Atypical hemolytic uremic syndrome is a rare disease characterized by low levels of circulating red blood cells due to their destruction (hemolytic anemia), low platelet count (thrombocytopenia) due to their consumption and inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a condition known as uremia.
  • Most aHUS are caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Signs and symptoms of aHUS can include, for example, feelings of illness, fatigue, irritability, and lethargy, anemia, thrombocytopenia, acute kidney failure, hypertension and organ damage.
  • Antiphospholipid syndrome is an autoimmune disease characterized by arterial and venous thrombosis due to antiphospholipid antibodies.
  • the disorder is referred to as primary when it occurs in the absence of another autoimmune disease.
  • Secondary APS occurs in the context of an autoimmune disorder such as systemic lupus erythematosus.
  • the catastrophic APS is a rare life-threatening form of APS in which widespread intravascular thrombosis results in multiorgan ischemia and failure.
  • MG Myasthenia gravis
  • Typical hemolytic uremic syndrome may follow a gastrointestinal infection with Shiga toxin-producing Escherichia coli (STEC).
  • Typical HUS (STEC-HUS; Shiga toxin- producing Escherichia coli (STEC)-hemolytic uremic syndrome (HUS)) can be initiated when the Shiga toxin (or Shiga-like toxin), a known potent cytotoxin, binds to cell membrane glycolipid Gb3 (via domain B). Domain A is internalized and subsequently halts protein synthesis and induces apoptosis of the affected cell.
  • the Shiga toxin has several additional effects on endothelial cells, one of which is enhanced expression of functional tissue factor that could contribute to microvascular thrombosis.
  • the toxin causes damage to or activation of endothelium, red cells, and platelets.
  • the present invention provides methods for administering an antagonist antigen-binding protein that binds specifically to C5 (e.g ., REGN3918) to a subject comprising (i) administering one or more doses (e.g., 1 dose) of about 30 mg/kg (body weight (BW)) of the antigen-binding protein (e.g., REGN3918) intravenously (IV); then, optionally, (ii) administering one or more doses (e.g., 2 or more) of about 800 mg of the antigen-binding protein (e.g., subcutaneously (SC)).
  • SC dose(s) may be given on a weekly basis following the initial IV dose(s).
  • the present invention also provides methods for administering an antigen-binding protein (e.g., REGN3918) to a subject comprising (i) administering one or more doses (e.g., 1 dose) of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally, (ii) administering one or more SC doses according to body weight as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; and for BW >60 kg: about 800 mg.
  • an antigen-binding protein e.g., REGN3918
  • SC dose(s) may be given on a weekly basis following the initial IV dose(s).
  • the subject is administered one or more doses of an oligonucleotide (e.g., cemdisiran) in association with the antigen-binding protein.
  • an oligonucleotide e.g., cemdisiran
  • the subject suffers from a C5-associated disease such as, for example, CHAPLE, PNH, aHUS or MG.
  • the present invention includes methods for treating or preventing a C5-associated disease such as PNH.
  • PNH can be diagnosed in a subject, for example, on the basis of:
  • PNH granulocytes (denoted as polymorphonuclear [PMN]) >10%.
  • Flow cytometry analysis of peripheral blood is a means for laboratory detection of PNH.
  • Flow cytometric immunophenotyping is performed to detect the presence or absence of GPI-linked proteins on granulocytes, monocytes, and erythrocytes, using fluorescently labeled monoclonal antibodies or FLAER (Fluorescein-Labeled Proaerolysin).
  • FLAER Fluorescein-Labeled Proaerolysin
  • FLAER is a fluorescently labeled variant of aerolysin that binds directly to the GPI anchor and can be used to evaluate the expression of the GPI linkage.
  • Proaerolysin is a 52-kDa protein secreted by Aeromonas hydrophila. After proteolytic nicking at the C-terminus, the active form, Aerolysin, is generated that binds to cell surface structures and oligomerizes, forming channels that result in cell lysis (Howard & Buckley, Activation of the hole-forming toxin aerolysin by extracellular processing. J. Bacteriol. 1985;163:336-340).
  • Aerolysin does not lyse PNH cells and it was shown that the toxin bound to the GPI moiety of GPI-linked structures (Diep et al., Glycosyl-phosphatidylinositol anchors of membrane glycoproteins are binding determinants for the channel-forming toxin aerolysin. J. Biol. Chem. 1998;273:2355-2360.25.; Brodsky et al., Resistance of paroxysmal nocturnal hemoglobinuria cells to the glycosylphosphatidylinositol-binding toxin aerolysin. Blood 1999;93:1749-1756). Initially, this reagent was used to enrich rare GPI- negative PNH clones.
  • PNH is characterized by chronic uncontrolled terminal complement activation and hemolysis.
  • Uncontrolled complement activation leads to red blood cell (RBC) hemolysis, platelet activation and subsequently thromboembolism (TE), renal and other organ impairment, pain, severe fatigue, poor quality of life and early mortality.
  • An indicator of cell lysis is the appearance of abnormally high levels of lactate dehydrogenase (LDH) in the serum.
  • LDH serum level of >1.5 or 2.0 x the upper limit of normal (LDH >1 5x; LDH >2.
  • Ox is a marker of uncontrolled complement activation that has been used in multinational PNH clinical trials.
  • Normal serum levels of LDH can vary depending on the laboratory and methods used for measurements; however, in children, the normal level is about 60-170 U/L and in adults it is about 100-190 U/L. Other reports have the normal adult LDH range as 140-280 U/L.
  • the normal female LDH ULN is 330 U/L and the male LDH ULN is 281 U/L. Having received one or more red blood cell transfusions, e.g., within 3 months, is also an indicator of PNH.
  • GPI-AP glycosyl phosphatidylinositol anchored protein
  • PMNs polymorphonuclear cells
  • Signs and symptoms of PNH also include fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin ⁇ 10 g/dL), a history of a major adverse vascular events (MAVE, including thrombosis), dysphagia, or erectile dysfunction.
  • CHAPLE disease for example, can be diagnosed on the basis of a genotype characterized by a biallelic CD55 loss-of-function mutation and persistent protein-losing enteropathy (PLE).
  • active CHAPLE disease can be identified in a patient exhibiting: hypoalbuminemia of less than or equal to 3.2 g/dL; and within the last 6 months and attributable to CD55-deficient PLE, at least 7 days (which do not have to be consecutive) of at least one of the following symptoms or signs: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection with concomitant hypogammaglobulinemia, or a new thromboembolic event.
  • CHAPLE disease may be based upon, e.g., primary intestinal lymphangiectasia or Waldmann’s disease, growth retardation, anemia, vitamin or micronutrient deficiency, Gl mucosal ulcer, Lymphoid infiltrates in Gl mucosa, recurrent lung infection, hypothyroidism, arthritis, arthralgia or finger clubbing.
  • primary intestinal lymphangiectasia or Waldmann’s disease e.g., primary intestinal lymphangiectasia or Waldmann’s disease, growth retardation, anemia, vitamin or micronutrient deficiency, Gl mucosal ulcer, Lymphoid infiltrates in Gl mucosa, recurrent lung infection, hypothyroidism, arthritis, arthralgia or finger clubbing.
  • Ozen et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis, New England J. of Med. 377(1):
  • the present invention includes methods for treating or preventing a C5-associated disease (e.g., PNH), in a subject, by
  • an antagonist antigen-binding protein that binds specifically to C5 e.g., antibody or antigen-binding fragment thereof; e.g., REGN3918
  • a dosing regimen of the present invention e.g., (i) administering one or more doses (e.g., 1 dose) of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally, (ii) administering one or more doses (e.g., 2 or more) of about 800 mg of the antigen-binding protein subcutaneously (SC).
  • SC doses are given on a weekly basis.
  • said signs and symptoms include LDH level > 1.5 or 2 c ULN; Type III PNH granulocytes > 10%; and/or signs and symptoms of active PNH disease.
  • the present invention includes methods for treating or preventing a C5-associated disease (e.g., CHAPLE), in a subject, by (i) evaluating the subject for the presence of signs and/or symptoms of the disease, e.g., CHAPLE, and, diagnosing the subject with the disease if one or more of such signs and/or symptoms are identified (e.g., as discussed herein); and
  • such signs and symptoms include loss-of- function mutation in the CD55 gene, flow cytometry or Western blot of peripheral blood cells to identify reduced presence of CD55, hypoalbuminemia of less than or equal to 3.2 g/dL and/or one or more of: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection with concomitant hypogammaglobulinemia, or a new thromboembolic event.
  • the present invention provides methods for treating or preventing a C5-associated disease comprising administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., ravulizumab, eculizumab, tesidolumab or mubodina) according to a dosing regimen of the present invention (e.g., (i) administering one or more doses of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally, (ii) administering either one or more weekly SC doses of about 800 mg of the antigen-binding protein; or one or more weekly SC doses according to body weight as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; and for BW >60 kg: about 800 mg; optional
  • an antagonist antigen-binding protein that binds specifically to C5 administered to a subject is in a pharmaceutical formulation that includes a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes one or more excipients.
  • a pharmaceutical formulation of the present invention is aqueous, i.e., includes water.
  • the pharmaceutical formulation comprises about 200 mg/ml antagonist antigen-binding protein that binds specifically to C5.
  • compositions including antagonist antigen-binding protein that binds specifically to C5 may be prepared by admixing the antigen-binding protein with one or more excipients (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al.
  • the further therapeutic agent is an oligonucleotide (e.g., DNA or RNA or a duplex of both), e.g., that binds to DNA or mRNA encoding C5 and inhibits C5 expression.
  • the oligonucleotide is up to about 23, about 19-22, about 19-23 or about 19, about 20, about 21 , about 22 or about 23 nucleotides in length (e.g., a 19-23 nucleotide RNA molecule).
  • the oligonucleotide is single stranded (e.g., in anti-sense orientation) or double stranded.
  • a double stranded oligonucleotide includes a strand in sense orientation and a strand in an anti-sense orientation.
  • the double stranded oligonucleotide e.g., RNA
  • the oligonucleotide is naked and in another embodiment the oligonucleotide is chemically modified.
  • the further therapeutic agent is an oligonucleotide which is an RNAi agent that binds to an RNA encoding C5 or a portion thereof.
  • An RNAi agent refers to an agent that contains RNA and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway.
  • RISC RNA-induced silencing complex
  • RNAi directs the sequence-specific degradation of mRNA through a process known as RNA interference.
  • the RNAi modulates, e.g., inhibits, the expression of C5 in a cell, e.g., a cell within a subject, such as a mammalian subject.
  • an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA.
  • a target RNA sequence e.g., a C5 target mRNA sequence
  • siRNA short- interfering RNA
  • Dicer Type III endonuclease
  • Dicer a ribonuclease-lll-like enzyme, processes the dsRNA into 19- 23 base pair short interfering RNAs (siRNAs) with characteristic two base 3' overhangs (Bernstein, et al., (2001) Nature 409:363).
  • siRNAs are then incorporated into an RNA- induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309).
  • RISC RNA- induced silencing complex
  • the invention Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188).
  • siRNA single stranded RNA
  • the term "siRNA” is also used herein to refer to an RNAi as described herein.
  • the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA.
  • single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA.
  • the single-stranded siRNAs are, in an embodiment of the invention, 15-30 nucleotides and are chemically modified. The design and testing of single- stranded siRNAs are described in U.S. Pat. No. 8,101 ,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894.
  • the oligonucleotide e.g., RNAi
  • RNAi is conjugated to another molecule such as a sugar, such as an N-acetylgalactosamine (GalNAc) derivative such as
  • the oligonucleotide e.g., RNAi
  • RNAi conjugated to another molecule as shown in the following schematic: wherein X is O or S.
  • the further therapeutic agent is cemdisiran.
  • the further therapeutic agent is a double stranded RNA comprising the anti-sense strand nucleotide sequence: (SEQ ID NO: 370); and/or the sense strand comprises the nucleotide sequence: (SEQ ID NO: 371).
  • the further therapeutic agent is a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises: (SEQ ID NO: 372) and the antisense strand comprises: (SEQ ID NO: 373), wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; and s is a phosphorothioate linkage; and wherein said sense strand is conjugated at the 3'-terminus to the ligand:
  • dsRNA double-stranded ribonucleic acid
  • the RNAi is in a pharmaceutical formulation comprising a lipid nanoparticle (LNP).
  • LNP is a vesicle comprising a lipid layer encapsulating a pharmaceutically active molecule such as RNAi.
  • LNPs are described in, for example, U.S. Pat. Nos. 6,858,225, 6,815,432, 8,158,601 , and 8,058,069, the entire contents of which are hereby incorporated herein by reference.
  • the further therapeutic agent is acetaminophen, albumin (e.g., in the form of an infusion), ancrod, an angiotensin-converting enzyme inhibitor, an antibiotic (e.g. an oral antibiotic), a further antibody, an anti-CD20 agent, rituximab, an anti-coagulant, an anti-fungal agent, an antihypertensive, an anti-inflammatory drug, antiplasmin-a1, an anti-seizure agent, anti-thrombotic agent, an anti-TNFalpha agent, an anti-viral agent, argatroban, aspirin, a biological therapeutic agent, bivalirudin, a C3 inhibitor, a corticosteroid, cyclosporine A, dabigatran, defibrotide, E-aminocaproic acid, enteral feeding, erythromycin, erythropoietin, a fibrinolytic agent , folic acid, fondaparinux, heparin, hormone replacement
  • an antibiotic e
  • serotypes A, C, Y, W and serotype B methotrexate, a non-steroidal anti-inflammatory drug (NSAID), an oligonucleotide, paracetamol, parenteral feeding, penicillin, phenindione, a pregnancy contraceptive drug, prostacyclin, rituximab, a thrombin inhibitor, a vaccine, vincristine, a vitamin and/or warfarin.
  • NSAID non-steroidal anti-inflammatory drug
  • composition e.g., including (1) an antagonist antigen-binding protein that binds specifically to C5 and pharmaceutically acceptable carrier components, along with (2) one or more further therapeutic agents, such as cemdisiran, can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit including each component, for example, wherein the further therapeutic agent is in a separate formulation).
  • an antagonist antigen-binding protein that binds specifically to C5 and pharmaceutically acceptable carrier components
  • further therapeutic agents such as cemdisiran
  • Components administered in association with each another can be administered to a subject at the same time or at a different time than when the other component is administered; for example, each administration may be given simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session) or non-simultaneously at one or more intervals over a given period of time. Moreover, the separate components administered in association with each another may be administered to a subject by the same or by a different route.
  • the present invention provides methods for treating or preventing C5-related disorders, in a subject, by administering an antagonist antigen-binding protein that binds specifically to C5 (e.g., REGN3918), e.g., (i) administering one or more doses of about 30 mg/kg (body weight (BW)) of the antigen-binding protein intravenously (IV); then, optionally, (ii) administering either one or more weekly SC doses of about 800 mg of the antigenbinding protein; or one or more weekly SC doses according to body weight as follows: for body weight (BW) ⁇ 10 kg: about 125 mg; for BW >10 kg and ⁇ 20 kg: about 200 mg; for BW >20 kg and ⁇ 40 kg: about 350 mg; for BW >40 kg and ⁇ 60 kg: about 500 mg; and for BW >60 kg: about 800 mg; wherein, optionally, the subject is further administering a therapeutically effective amount of oligonucleotide that binds to a polyn
  • a therapeutically effective dose of a dsRNA, RNAi or other oligonucleotide that binds a polynucleotide encoding C5 and inhibits expression of C5 will, in an embodiment of the invention, be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day.
  • a dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose.
  • a C5 dsRNA is administered at a dose of about 0.1 to about 20 mg/kg, about 0.1 to about 30 mg/kg, about 0.1 to about 40 mg/kg, about 0.1 to about 45 mg/kg, about 0.1 to about 50 mg/kg, about 0.25 to about 20 mg/kg, about 0.25 to about 30 mg/kg, about 0.25 to about 40 mg/kg, about 0.25 to about 45 mg/kg, about 0.25 to about 50 mg/kg, about 0.5 to about 20 mg/kg, about 0.5 to about 30 mg/kg, about 0.5 to about 40 mg/kg, about 0.5 to about 45 mg/kg, about 0.5 to about 50 mg/kg, about 0.75 to about 20 mg/kg, about 0.75 to about 30 mg/kg, about 0.75 to about 40 mg/kg, about 0.75 to about 45 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 20 mg/mg, about 1 to about 30 mg/mg, about 1 to about 40 mg/mg, about 1 to
  • the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg.
  • the C5 dsRNA or RNAi or other oligonucleotide may be administered e.g., subcutaneously or intravenously, at a dose (or repeated doses) of about 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1 , 1.2, 1.3, 1.4,
  • a multi-dose regimen may include administration of a therapeutic amount of C5 dsRNA or RNAi or other oligonucleotide daily, such as for two days, three days, four days, five days, six days, seven days, or longer.
  • a repeat-dose regimen may include administration of a therapeutic amount of C5 dsRNA or RNAi or other oligonucleotide on a regular basis, such as every other day, every third day, every fourth day, twice a week, once a week, every other week, or once a month.
  • a C5 dsRNA or RNAi or other oligonucleotide may be administered e.g., subcutaneously or intravenously, at a dose (or repeated doses) of about 600 mg.
  • a pharmaceutical composition including an oligonucleotide can be administered by intravenous infusion over a period of time, such as over a 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
  • the administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer.
  • a regular basis such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer.
  • the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer.
  • compositions and methods set forth in the Examples form part of the present invention.
  • Example 1 An Open-Label, Single Arm Study to Evaluate the Efficacy and Safety of REGN3918 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Complement Inhibitor-Naive or Have Not Recently Received Complement Inhibitor Therapy
  • PNH Paroxysmal Nocturnal Hemoglobinuria
  • the primary objective of the study is to demonstrate a reduction in intravascular hemolysis by REGN3918 over 26 weeks of treatment in patients with active PNH who are treatment-naive to complement inhibitor therapy or have not recently received complement inhibitor therapy.
  • the secondary objectives of the study are to evaluate the safety and tolerability of REGN3918; to evaluate the effect of REGN3918 on parameters of intravascular hemolysis; to assess the concentrations of total REGN3918 in serum; to evaluate the incidence of treatment-emergent anti-drug antibodies to REGN3918; and to evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life.
  • the duration of the study for a patient is approximately 27 weeks, excluding the screening period.
  • the study consists of a screening period (up to 4 weeks), 26 week treatment period, and an end-of-study visit one week after the last study drug administration. After completion of the 26 week treatment period, patients may enroll into a separate open label extension study, which will provide uninterrupted treatment with REGN3918. Patients who discontinue treatment will have a minimum of a 21 week follow up period.
  • the study population will consist of adult male and female patients with confirmed diagnosis of PNH and active signs and symptoms who either are complement inhibitor-na ' ive or have received prior treatment with a complement inhibitor, but not within 6 months prior to screening visit.
  • a patient must meet the following criteria to be eligible for inclusion in the study: 1. Male or female > 18 years of age or legal age of majority at screening, whichever is greater;
  • PNH granulocytes (denoted as polymorphonuclear [PMN]) > 10% at screening visit;
  • Active disease as defined by the presence of 1 or more PNH related signs or symptoms (e.g., fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin ⁇ 10 g/d L] , history of a MAVE (major adverse vascular events) [including thrombosis], dysphagia, or erectile dysfunction) or history of RBC transfusion due to PNH within 3 months of screening;
  • PNH related signs or symptoms e.g., fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin ⁇ 10 g/d L]
  • MAVE major adverse vascular events
  • dysphagia including thrombosis
  • erectile dysfunction or history of RBC transfusion due to PNH within 3 months of screening
  • Planned modification initiation, discontinuation, or dose / dosing interval change
  • background concomitant medications as applicable, during screening and treatment periods: erythropoietin, immunosuppressive drugs, corticosteroids, antithrombotic agents, anticoagulants, iron supplements, and folic acid;
  • ANC Peripheral blood absolute neutrophil count
  • Highly effective contraceptive measures include: a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening b. intrauterine device (IUD); intrauterine hormone releasing system (IUS) c. bilateral tubal ligation d. vasectomized partner e. and/or sexual abstinence ⁇ *;
  • Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception.
  • Female condom and male condom should not be used together; or
  • hepatitis B or C defined as a testing history showing a currently positive status for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA, or hepatitis C virus RNA (HCV RNA).
  • HBV RNA hepatitis C virus RNA
  • the co-primary endpoints are:
  • the secondary endpoints are:
  • Serum Lactate Dehydrogenase Serum Lactate Dehydrogenase (LDH). Samples for LDFI testing will be collected at visits. Serum LDFI levels will the measured in a central lab. On days when Blood Chemistry is run, then LDFI will be included in the panel which will also be run in a central lab. For patients who self-administer, samples may be drawn at home by the visiting nurse when scheduled on non-clinic visits.
  • Transfusion Record Update Patients will be requested to provide updated information about the history of transfusions received 1 year prior to the time of screening. During the study, the rate and number of units of transfusion with RBCs will be recorded in the case report form (CRF). Transfusions with RBCs during the study should follow the algorithm described herein. The rate and number of units of transfusion with RBCs will be recorded in the CRF. Flemoglobin levels pre- and post-transfusion will be obtained (including local values).
  • Samples for CFI50 testing will be collected at visits. Serum CFI50 levels will the measured in a central lab. For patients who self-administer, samples may be drawn at home by the visiting nurse when scheduled on non-clinic visits.
  • Red Blood Cell Hemoglobin Red blood cell hemoglobin testing will be measured in a safety hematology panel collected at visits and will be run in a central lab. Free Hemoglobin. Free hemoglobin testing will be measured in the safety hematology panel collected at visits and will be run in a central lab.
  • COAs Clinical Outcome Assessments.
  • the COAs are patient self-reported.
  • Clinical outcome assessments will include the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and 2 health-related quality of life (FIRQoL) questionnaires (EORTC quality of life questionnaire-core 30 [QLQ-C30] and the EQ-5D-3L) and Patient Global Impression of Severity (PGIS)/Patient Global Impression of Change (PGIC).
  • the FACIT Fatigue is a 13 item, self-reported PRO measure assessing an individual’s level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health related QoL in patients with cancer and other chronic illnesses.
  • the FACIT Fatigue assesses the level of fatigue using a 4 point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
  • the FACIT Fatigue was originally developed to assess fatigue in patients with cancer, it has been used in trials evaluating the efficacy of eculizumab.
  • the FACIT Fatigue has demonstrated content validity among patients with PNFI.
  • the EORTC QLQ C30 is a 30 item, generic questionnaire commonly used to assess FIRQoL in patients with cancer (Stead et al., Development of an EORTC questionnaire module to be used in health-related quality-of-life assessment for patients with multiple myeloma. European Organization for Research and Treatment of Cancer Study Group on Quality of Life. Br J Flaematol 1999; 104(3):605-11 ; Cocks et al., An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 2007;
  • the EORTC QLQ C30 assesses FIRQoL across multiple domains, including global health status, global quality of life, functioning (physical, role, emotional, cognitive, and social functioning), symptom scales (fatigue, nausea and vomiting, pain, appetite loss), and single items (dyspnea, insomnia, constipation, diarrhea, sleep, financial impact). Although the EORTC QLQ 30 was originally developed to assess HRQoL in patients with cancer, it has been used in trials evaluating the efficacy of eculizumab.
  • the EORTC QLQ also has demonstrated content validity among patients with PNH (Brodsky et al., Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111(4): 1840-7; Hillmen et al., The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355(12):1233-43).
  • the EORTC QLQ also has demonstrated content validity among patients with PNH (Weitz et al., Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern Med J 2013; 43(3):298-307.).
  • the EQ-5D-3L is a self-administered, generic standardized health status measure, consisting of 6 questions.
  • the EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-level scale: no problems, some problems, and extreme problems.
  • the EQ visual analog scale component is a vertical, visual analog scale used by patients to rate their health.
  • Patient Global Impression of Severity/Patient Global Impression of Change consists of 3 self-administered PRO questions assessing the patient’s perception of the overall severity of the symptoms of their disease and/or of a specific symptom of their disease.
  • patients will be asked to rate the severity of their PNH symptoms on a 6-point Likert scale ranging from "I am not experiencing PNH symptoms” to "very severe”; the impact their PNH symptoms have on their ability to perform usual daily activities on a 5-point Likert scale ranging from “not at all impacted” to “extremely impacted”; and their overall fatigue on a 5-point Likert scale ranging from “not fatigued” to "extremely fatigued”.
  • Patient Global Impression of Change consists of 3 self-administered PRO questions assessing the patient’s perception of the change in overall severity of the symptoms of their disease and/or of a specific symptom of their disease compared to the start of the study.
  • patients will be asked to rate the change in PNH symptoms, in their ability to perform usual daily activities, and in overall fatigue compared to before the start of the study on a 7-point Likert scale ranging from "much better” to "no change" to "much worse”.
  • PGIS and PGIC questions are developed for this trial and allow for the interpretation of PRO findings and the investigation of a responder definition.
  • the answers on the PGIS and PGIC items serve as “anchors” to help interpret the mean change in disease-specific PRO measures over time and to estimate responder definitions.
  • This empirical anchor-based approach is the primary FDA-recommended approach for defining a responder and analyzing responder-based PRO results.
  • Patients will be given a single loading dose of REGN3918 30 mg/kg intravenous (IV) on day 1, then a dose not greater than 800 mg subcutaneous (SC) once weekly (QW; ⁇ 1 day) to week 26.
  • IV intravenous
  • SC subcutaneous
  • the PK variable is the concentration of total REGN3918 at each time point.
  • the sampling time points are specified in Table 1-1.
  • the anti-drug antibody (ADA) variables are ADA status, titer, and time point/visit. Samples in this study will be collected at the clinic visits specified in Table 1-1. Blood samples for ADA assessment in serum will be collected prior to drug administrations.
  • subsequent administrations may either be continued at the clinical site, or by the site personnel or another healthcare professional at patient’s home (if possible), or self- administered/administered by the patient or designated person, respectively.
  • Patients will be given a single loading dose of REGN3918 30 mg/kg IV on day 1 , then a dose no greater than 800 mg SC QW ( ⁇ 1 day) over the treatment period.
  • the weekly subcutaneous dose is 800 mg SC QW ( ⁇ 1 day) for the initial cohort A patients.
  • subsequent administrations may be continued at the clinic site, at the patient’s home by another healthcare professional, or by the patient/designated person.
  • SC route of administration will depend on the preference of the investigator and patient (e.g., abdomen, thigh, or upper arm), the availability of clinical supply, and home healthcare visiting professional. Clinic visits for SC administration may or may not be needed.
  • Transfusions with RBCs during the study should proceed according to the following predefined criteria that will trigger a transfusion; however, the actual number of units to be transfused is at the discretion of the investigator:
  • Enrolled patients will require evidence of meningococcal immunization or administration of vaccination during the screening period and oral antibiotics are recommended during the treatment period, according to local practice.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • AST aspartate aminotransferase
  • ALT or AST aspartate aminotransferase
  • AST aspartate aminotransferase
  • ALT or AST > 8 x ULN
  • ALT or AST > 5 x ULN for more than 2 weeks
  • o ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or international normalized ratio (INR) > 1.5) and no other reason can be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable of causing the observed injury;
  • Patient non-compliance e.g ., not complying with protocol required visits, assessments, and/or dosing instructions
  • Temporary discontinuation may be considered by the Investigator because of suspected AEs.
  • the investigator can reinitiate treatment with study drug under close and appropriate clinical and/or laboratory monitoring once the Investigator will have considered according to his/her best medical judgment that the responsibility of the study drug in the occurrence of the concerned event was unlikely.
  • the infusion should be interrupted if any of the following AEs are observed: cough, rigors/chills, rash, pruritus (itching), urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), vomiting, flushing.
  • the reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the original rate. If investigators feel there is a medical need for treatment or discontinuation of the infusion other than described above, they should use clinical judgment to provide the appropriate response according to typical clinical practice.
  • the infusion should be terminated and NOT restarted if any of the following AEs occur: anaphylaxis * , laryngeal/pharyngeal edema, severe bronchospasm, chest pain, seizure, severe hypotension, other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, etc); or any other symptom or sign that, in the opinion of the investigator, warrants termination of the IV infusion ‘
  • anaphylaxis if the following is observed (Sampson et al., Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
  • Acute systemic reactions following injection of study drug (SC) should be treated using clinical judgment to determine the appropriate response according to typical clinical practice. Local injection site reactions must be reported as AEs and graded.
  • EORTC European Organization for Research and Treatment of Cancer
  • QLQ C30 Quality of life questionnaire core 30
  • PGIS Patient global impression of severity
  • PGIC Patient global impression of change
  • EQ 5D 3L Euroquol EQ-5D 3 level questionnaire
  • the last available HB after transfusion was 11.8 g/dL on Day 57. This transfusion is considered to be a per protocol transfusion.
  • the serum concentration of REGN3918 was also evaluated in the subjects. See Figure 9 and Figure 10. Individual subjects’ and median REGN3918 serum concentrations over time are shown in normal scale as well as in semi-log scale ( Figures 9A, 9B, 10A and 10B). These data are also broken down by gender ( Figures 9C, 9D, 10C and 10D).
  • the data set forth in the present example provides evidence that REGN3918 has properties which are advantageous over that of ALXN1210 and eculizumab. Though the data herein is from only 6 patients, 100% (6 out of 6) of the patients normalized their LDFI serum levels. In the studies set forth in Figure 25, only about half of the patients on ALXN1210 or eculizumab achieved LDFI normalization.
  • Example 2 A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of the Pharmacokinetics and Pharmacodynamics of REGN3918, a Human Antibody against Complement Factor C5, in Healthy Volunteers
  • REGN3918 (pozelimab), is a fully human monoclonal immunoglobulin antibody directed against the terminal complement protein C5 which inhibits terminal complement activation by blocking C5 cleavage, thereby blocking the formation of the membrane attack complex (MAC; C5b-9).
  • REGN3918 binds with high affinity to wild-type and variant (R885H/C) human C5.
  • REGN3918 was well-tolerated in monkey toxicology studies with up to 26 weeks of dosing at up to 100 mg/kg/wk. This finding was supportive of conducting this first-in-human (FIH) study of REGN3918 in healthy volunteers.
  • the primary objective of this study was to evaluate the safety and tolerability of REGN3918 administered in healthy volunteers, using both single ascending IV and SC doses and a multiple dose regimen consisting of an IV loading dose plus multiple weekly SC doses.
  • the secondary objectives of this study were to assess the pharmacokinetic and pharmacodynamic profile of REGN3918.
  • Cohort 4 30 mg/kg IV, single dose
  • Cohort 5 Loading dose of 15 mg/kg IV followed by 4 repeat SC doses of 400 mg administered once weekly for 4 weeks.
  • Table 2-1 Summary of Demographic and Baseline Characteristics of Subjects by REGN3918 Dose Regimen and Route of Administration a Pool of all administration types. b Multiple dose study drug administration given as single dose of 15 mg/kg IV + 400 mg SC once weekly for 4 weeks.
  • REGN3918 exhibited dose-dependent increases in exposure in serum, with a trend toward prolonged serum concentrations at IV doses >10 mg/kg ( Figure 2). Following SC administration, concentrations of REGN3918 in serum peaked at 4-8 days post-dose, and bioavailability was estimated as approximately 70%. REGN3918 exposure led to dose- dependent inhibition of CH50. In all 4 IV dosing cohorts, suppression of hemolysis was observed at 15 minutes post-injection. Maximal suppression of hemolysis was achieved with >3 mg/kg dosing. At 30 mg/kg, maximal suppression of hemolysis was maintained for >4 weeks, consistent with observed prolonged REGN3918 concentrations following this dose.
  • REGN3918 was found to be well tolerated in single doses of up to 30 mg/kg IV and 600mg SC (Table 2-2).
  • the multiple dose Cohort 5 has completed dosing in all subjects and has completed all safety follow-up.
  • Table 2-2 Overview of Treatment-Emergent Adverse Events (TEAEs) a Pool of all administration types.
  • TEAEs Treatment-Emergent Adverse Events
  • b Multiple dose study drug administration given as single dose of 15 mg/kg IV + 400 mg SC once weekly for 4 weeks.
  • MedDRA MedDRA (Version 21.0) coding dictionary applied. IV, intravenous; SC, subcutaneous; TEAE, treatment-emergent adverse event.
  • REGN3918 was generally well tolerated in both single ascending IV and SC dose administration as well as in a single IV loading dose followed by 4 consecutive weekly dose administrations. Rapid and maximal suppression of complement activity as measured by the sheep red blood cell CH50 assay was demonstrated for IV doses with >3 mg/kg dosing. At 30 mg/kg, maximal suppression of hemolysis was maintained for >4 weeks. A regimen of 15 mg/kg IV loading dose followed by 4 consecutive weekly 400 mg SC doses maintained suppression of CH50 throughout the dosing period and 2 weeks post the last dosing.
  • the alternative pathway (AP) and classical pathway (CP) hemolysis assays were performed based on lysis of rabbit red blood cells (RBCs) and sensitized sheep RBCs, respectively. Both assays measure the amount of hemoglobin released from red blood cells at 412 nm.
  • Magnesium is an important cofactor for the activity of AP C3 and C5 convertases.
  • magnesium concentration could change, which would affect the converatse function.
  • serum percentage 10, 25 or 48%)
  • magnesium concentration could change, which would affect the converatse function.
  • MgCh Magnesium concentration at 1 , 1.5 or 2 mM did not affect the individual antibody performance.
  • the relative differences among three antibodies tested still existed at three different concentrations of magnesium. While magnesium concentration may still be a contributing factor, under the conditions tested, there seems to be other mechanisms that may be responsible for the relative differences observed.
  • Example 3 Switching from Eculizumab to REGN3918 Results in Normalization of C5 Concentrations in C5 hu/hu Mice and Sustained Suppression of Hemolytic Activity Ex Vivo.
  • mice were administered three doses of 15 mg/kg of REGN3918 or eculizumab (SEQ ID NOs: 358 and 359) on days 0, 15 and 29.
  • One group received REGN3918 only for all three doses, while a second group received eculizumab only.
  • the third group, the ‘switch group’ received eculizumab on day 0 and was then switched to REGN3918 on days 15 and 29.
  • Cage-side observations and routine wellness checks showed mice to be healthy with all animals surviving until their scheduled date of termination.
  • Serum C5 concentrations were also monitored. In mice administered REGN3918, serum concentrations of C5 increased to a maximum of 1.4-fold over the duration of the study. In contrast, eculizumab induced higher concentrations of serum C5 after the first, second and third doses (1.9, 2.0 and 2.8-fold increases, respectively) ( Figure 26(B)). The first dose of eculizumab administered to the ‘switch group’ induced a similar increase in serum C5 concentrations as in animals that received eculizumab alone.
  • REGN3918 eculizumab and C5 complexes predominantly contain 1 to 2 molecules of C5.
  • REGN3918 has can be a viable therapeutic option for patients that carry rare genetic variants of C5 and may also provide an alternative for patients currently treated with eculizumab.
  • combining antibodies that bind unique epitopes on a soluble antigen has the potential to generate higher order protein complexes, which can elicit type III hypersensitivity reactions similar to serum sickness.
  • Such conditions are likely to be self- limiting and the size of the complexes will be influenced by the molar ratio of the antibodies and antigen, with the largest complexes generally forming when the components are at or near equimolar amounts.
  • REGN3918 In addition to providing a viable therapeutic option for patients carrying rare C5 variants, REGN3918 also offers an alternative to patients currently treated using eculizumab. For example, REGN3918 may require less frequent dosing regimens and result in more stable serum C5 levels. Dose switching studies in humanized C5 mice demonstrated that switching treatments from eculizumab to REGN3918 was well tolerated and maintained suppression of complement activity. However, combining antibody therapeutics against a soluble antigen has the potential to generate higher order, immunogenic protein complexes.
  • Example 4 An Open-Label Efficacy and Safety Study of Pozelimab in Patients with CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease)
  • Patients will be given a single loading dose of Aerosol (IV) on day 1, then fixed doses subcutaneously (SC) (based on body weight) QW ( ⁇ 1 day) over the treatment period.
  • the study includes a screening period (up to 4 weeks) followed by a 104-week treatment period from week 0 to week 103, and a follow-up period from week 104 to week 116. Only patients with active PLE will be included in the primary analysis.
  • active PLE is defined as hypoalbuminemia of less than or equal to 3.2 g/dL within the screening period, and within the last 6 months, at least 7 days (which do not have to be consecutive) of 1 or more of the following symptoms or signs: diarrhea, vomiting, abdominal pain, peripheral or facial edema, an episode of infection with concomitant hypogammaglobulinemia, or a new thrombotic event. Study duration
  • the duration of the study for a patient is approximately 117 weeks (from week 0 to week 116), excluding the screening period.
  • Sample Size A minimum of 6 patients with active PLE will be enrolled. Following this, enrollment will be closed 1 year after the FPFD or upon enrollment of the 20th patient, whichever is earlier. Eligible patients with inactive PLE may also be enrolled, but their data will not be included in the primary analysis.
  • Target Population Patients aged 1 year and older with a clinical diagnosis of CD55- deficient PLE disease, with CD55 loss of function mutation determined by genetic analysis (frameshift, nonsense mutations) and confirmed (only necessary in the case of missense or suspected splice site mutations) by flow cytometry or western blotting CD55 on peripheral blood cells. The first 2 patients must be aged 6 years and older (exception will be made for patients under 6 years of age with life-threatening disease).
  • Table 4-1 Demographics and Other Baseline Characteristics of Four Patients in the Clinical Trial.
  • Subjects are identified by anonymous numeric ID.
  • CD55-deficient PLE/CFIAPLE disease (based on a history of PLE), confirmed by biallelic CD55 loss-of-function mutation detected by genotype analysis (frameshift, nonsense mutations). In the case of missense or suspected splice site mutations, CD55-deficient PLE is to have been confirmed by flow cytometry of peripheral blood cells or western blot. These diagnostic tests can be performed as part of the study screening procedures, or as part of standard clinical evaluation prior to screening;
  • a concomitant disease that leads to secondary intestinal lymphangiectasia such as a fontan procedure for congenital heart disease.
  • Patients known to have had hepatitis B or C in the past can enroll only if these diseases are no longer active, as demonstrated by negative hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA, and negative hepatitis C virus RNA (HCV RNA), respectively.
  • Testing for hepatitis B and C is not mandatory for enrollment in the trial but may be performed at the discretion of the investigator.
  • Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening b. Intrauterine device (IUD); intrauterine hormone-releasing system (IUS) c. Bilateral tubal ligation d. Vasectomized partner e. And/or sexual abstinence ⁇ , ⁇ .
  • Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
  • Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.
  • the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
  • Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception.
  • Female condom and male condom should not be used together.
  • TB unresolved tuberculosis
  • LTBI latent tuberculosis infection
  • the primary endpoint is the proportion of patients achieving both of the following:
  • Improvement is defined as a reduction of 50% or more in the number of daily bowel movements based on a 1-week average.
  • Patients evaluable for improvement are defined as those with an average of 3 or more bowel movements per day at baseline. Worsening is defined as an increase of 30% or more.
  • Improvement is defined as a reduction of 2 points or more.
  • Patients evaluable for improvement are defined as those with a severity of at least 2 points out of 5 at baseline. Worsening is defined as an increase of 2 points or more.
  • Improvement is defined as a reduction of 2 points or more.
  • Patients evaluable for improvement are defined as those with a severity of at least 2 points out of 5 at baseline. Worsening is defined as an increase of 2 points or more.
  • Improvement is defined as an increase of 6 points or more (on the 0 to
  • the secondary endpoints are:
  • - Improvement in stool consistency will be defined as a reduction of >50% in the number of days per week that the patient has a bowel movement of loose/watery consistency.
  • a bowel movement is considered to be loose/watery if it corresponds to 3 images of loose or watery stools on the Brussels Infant and Toddler Stool Scale (BITSS), the images and descriptors for categories 4 or 5 on the modified Bristol Stool Form Scale for Children (mBSFS-C), and the images and descriptors for categories 6 or 7 of the Bristol Stool Form Scale (BSFS).
  • BITSS Brussels Infant and Toddler Stool Scale
  • mBSFS-C modified Bristol Stool Form Scale for Children
  • BSFS Bristol Stool Form Scale
  • serum albumin defined as serum albumin within the normal range at at least 70% of measurements between week 12 and week 48 (and between week 12 and week 104); and no single albumin measurement of
  • serum albumin defined as serum albumin within the normal range at at least 70% of measurements between week 12 and week 24 (and between week 12 and week 48, between week 12 and week 104); and no single albumin measurement of ⁇ 2.5 g/dL between week 12 and week 24 (and week 48, week 104); and no requirement for albumin infusion between week 12 and week 24 (and week 48, week 104); and
  • Vitamin B12 folate, iron, iron binding capacity, ferritin, magnesium, fasting cholesterol/triglycerides, expressed as:
  • the exploratory outcomes are:
  • Serum Albumin Serum Albumin, Total Protein, and Immunoglobulin. Samples will be collected and tested in the blood chemistry or immunoglobin panel at a lab.
  • Physicians will assess peripheral edema as follows: Following a general inspection and palpation of all 4 limbs, the investigator will rate the overall severity of peripheral edema taking into account both degree and distribution, on a 5-point rating scale, where 1 signifies no edema and 5 signifies very severe edema.
  • CD55-deficient PLE This is an open-label, single-arm, 104-week treatment study in patients aged 1 year and older with active clinical signs and symptoms of CD55-deficient PLE/CHAPLE disease, and a CD55 loss-of-function mutation detected by genotype analysis (frameshift, nonsense mutations).
  • CD55-deficient PLE is to be confirmed by flow cytometry of peripheral blood cells. The first 2 patients enrolled will be of age 6 or older (exception will be made for patients under 6 with life threatening disease).
  • a minimum of 6 patients with active PLE will be enrolled. Following this, enrollment will be closed 1 year after the first patient first dose (FPFD) or upon enrollment of the 20th patient, whichever is sooner. The primary analysis will occur when approximately 6 patients with active PLE have received 6 months of treatment. Subsequent analyses will occur 1 and 2 years after the first dose in the last patient enrolled.
  • FPFD first patient first dose
  • the study consists of a screening period (up to 4 weeks) followed by a 104-week treatment period from week 0 to week 103, and a follow-up period from week 104 to week 116. Following the end of the treatment period, patients may have the option to enroll in an open-label extension study, to last until approval of commercialization of sodalimab in their country if this has not already occurred, or until termination of commercialization/development of sodalimab.
  • Active PLE is defined as hypoalbuminemia of less than or equal to 3.2 g/dL within the screening period, and within the last 6 months, at least 7 days (which do not have to be consecutive) of one or more of the following symptoms or signs: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode of infection with concomitant hypogammaglobulinemia, or a new thrombotic event. Active patients should not be on current therapy with eculizumab.
  • Pozelimab drug product will be provided in a sterile, single-use glass vial for either IV or SC administration and will be supplied by the sponsor.
  • Drug product will be initially provided in lyophilized form in a sterile, single use glass vial for IV or SC administration that requires reconstitution with sterile water for injection, and then transitioned to a sterile, single-use glass vial or pre-filled syringe containing a liquid 200 mg/mL Polimab formulation for IV or SC administration that will not require reconstitution.
  • Study drug will be supplied by the sponsor.
  • the admixture solutions needed for delivery of the lyophilized or liquid drug product for IV administration will be sourced locally, or may be supplied by the sponsor, as necessary.
  • the location and administration options for the SC route of administration will depend on the preference of the investigator and patient (e.g., abdomen, thigh, or upper arm), the availability of clinical supply, and home healthcare visiting professional. Clinic visits for SC administration may or may not be needed. If self-administration/administration by patient/designated person is allowed locally, then sufficient injection training at the scheduled injection with Polimab will be provided. After training, observation of self-administration/administration by patient/designated person will be conducted by clinical site personnel or visiting healthcare professional. Once this observation is considered satisfactory, then the study drug can be subsequently administered independently by patient/designated person for the remainder of the study.
  • a patient diary will be provided prior to initiation of self-administration (i.e., day 29). The diary should be completed upon each study drug administration.
  • a study drug kit will be dispensed at the clinical site visit, using a direct-to-patient (DTP) service provider, or transported by a healthcare professional, as applicable. Detailed information about the study drug administration is provided in the pharmacy manual.
  • DTP direct-to-patient
  • the PK endpoint is concentration of total Aerosol and Blood.
  • Anti-drug antibodies will be characterized by the type and level of the observed response. Samples positive in the ADA assay will be further characterized for neutralizing antibodies (NAbs) and ADA titers.
  • Anti-drug antibodies response categories and titer categories that will be assessed are as follows:
  • Titer value category (titer range);
  • Enrolled patients will require evidence of meningococcal immunization or administration of vaccination during the screening period, and oral antibiotics are recommended during the treatment period, according to local or national practice and investigator’s assessment.
  • Vaccinations Enrolled patients will require immunization with meningococcal vaccinations. Administration of vaccination should occur preferably at least 2 weeks prior to initiation of Polimab, or at another time point according to local practice or national guidelines. It is suggested that patients undergo vaccination for serotypes A, C, Y, W, and, if available, serotype B. Patients who have had previous, documented vaccination for meningococcus will be re-immunized based on local practice. Patients should be closely monitored for early signs and symptoms of meningococcal infection and evaluated immediately if an infection is suspected. Patients will be provided with a patient safety card describing signs and symptoms of meningococcal infection along with instructions in case of a potential meningococcal infection, as well as information for the non-investigator healthcare provider.
  • oral antibiotic prophylaxis may commence on the day of first dosing, unless the risks outweigh the benefits or it is inconsistent with local practice, and continue for the duration of the study. It is recommended that patients who prematurely discontinue Aerolimab receive at least 21 weeks of oral antibiotic prophylaxis after discontinuing Polimab, or a duration consistent with local guidelines, whichever is longer. For adults, it is suggested that antibiotic prophylaxis be penicillin V 500 mg twice a day (BID), and in the case of penicillin allergy, erythromycin 500 mg BID may be used at the discretion of the investigator.
  • BID penicillin V 500 mg twice a day
  • antibiotic prophylaxis be penicillin VK 125 mg orally BID in patients who are ⁇ 5 years of age, and 250 mg BID if > 5 years of age. If pediatric patients are penicillin-allergic, then erythromycin 125 mg orally BID in patients who are ⁇ 3 years of age and 250 mg orally BID in patients who are > 3 years of age.
  • the decision to administer prophylaxis with oral antibiotics, the duration of prophylaxis, the choice and dosage regimen of oral antibiotics will be at the discretion of the investigator.
  • the oral antibiotics will be sourced locally by the investigator or designee and reimbursed by the sponsor.
  • Dose Modification is not allowed for an individual patient. Patients will increase dose as specified by the dose regimen in the event that they move into a higher BW bracket. For the purposes of these dose increases, body weight will be measured at the study visits as specified in the schedule of assessments and not at each weekly administration. Pozelimab will be supplied initially in vials as lyophilized powder for reconstitution, so a single presentation will support all the weight-based dosing regimen. The correct number of vials and volume for SC injection drawn up will be administered by a healthcare practitioner (not necessarily a doctor) at the study site, during a visit, or at a local primary healthcare clinic in between visits or at home; selfadministration/administration by patient/designated person may also be allowed.
  • a healthcare practitioner not necessarily a doctor
  • Each SC dose may be administered by more than one injection if necessary; each injection should not exceed a 2 ml_ volume.
  • Study Drug Discontinuation Patients who permanently discontinue from study drug and who do not withdraw from the study will be asked to return to the clinic for all remaining study visits per the visit schedule. Patients who permanently discontinue from study drug and who opt to withdraw from the study may be asked to complete study assessments.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • - ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or international normalized ratio [INR] > 1.5) and no other reason can be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury;
  • Patient noncompliance e.g., not complying with protocol-required visits, assessments, and/or dosing instructions
  • Temporary discontinuation may be considered by the investigator because of suspected AEs.
  • the investigator can reinitiate treatment with study drug under close and appropriate clinical and/or laboratory monitoring once the investigator will have considered, according to his/her best medical judgment, that the responsibility of the study drug in the occurrence of the concerned event was unlikely.
  • Management of Acute Reactions
  • the infusion should be interrupted if any of the following AEs are observed:
  • reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the original rate.
  • Respiratory compromise e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia
  • Local injection site reactions must be reported as AEs and graded according to the Food and Drug Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
  • FDA Food and Drug Administration
  • Any treatment administered from the time of informed consent to the end of the final study visit will be considered concomitant medication. This includes medications that were started before the study and are ongoing during the study.
  • Permitted medication is any medication that is not prohibited.
  • Albumin infusions are permitted during screening only for disease of life-threatening severity and after start of study drug in the event that the albumin level is below 3.0 g/dL with accompanying symptoms of facial or peripheral edema or ascites. This limitation only applies to albumin infusions given specifically for the PLE.
  • Any medication required to treat an AE including non-steroidal anti-inflammatory drugs, antihistamines, or topical or systemic corticosteroids, at the discretion of the investigator;
  • Oral contraceptives or hormone replacement therapy may continue or be started during the study
  • Immunosuppressive drugs biologic therapies, immunoglobulins, corticosteroids, anti-thrombotic agents, anticoagulants, antibiotics, iron supplements, vitamins, and enteral and parenteral feeding are permitted. Any changes to these concomitant medications will be at the discretion of the investigator. Weaning and/or withdrawal of any of these medications is permitted at the discretion of the investigator, in the context of response in the underlying disease to treatment with sodalimab; or
  • CGIS Clinical global impression of severity
  • CGIC Clinical global impression of change
  • PT prothrombin time
  • APTT activated partial thromboplastin time
  • BITSS Brussels infant and toddler stool scale
  • BSFS Bristol stool form scale
  • mBSFS-C modified Bristol Stool Form Scale for Children
  • ADA -anti-drug antibody
  • PedsQL Pediatric Quality of Life Inventory
  • Treatment period is from first dose at week 0 to last dose at week 103. All visits in the Schedule of Events table are mandatory in-clinic visits, and do not reflect the dosing schedule, which is weekly. Study procedures within each visit may be conducted on different days, within the stated visit window.
  • Neisseria gonorrhea prevention and regular testing should be advised for at-risk patients, as applicable.
  • a risk factor assessment should be based on local practice or national guidelines. The investigator should make his/her own assessment of risk (and if needed, consultation with other healthcare provider) to determine if the patient is at risk, which would lead to further management on prevention, testing, and treatment of Neisseria gonorrhea. Testing and treatment should be in accordance with local practice/national guidelines. General preventive measures include abstinence and use of a condom. Additional preventive measures should be considered based on local practice or national guidelines. 8. Screening by tuberculin skin test or T-cell interferon-gamma release assay may be performed according to local practice or guidelines at the discretion of the investigator.
  • Hematology, chemistry (except Total C5, CH50 sC5b-9 and C5a), urinalysis, and pregnancy testing samples may be analyzed by a local/central laboratory. Other testing will be done by a central or specialized laboratory as outlined in the sample management plan. Detailed instructions for blood sample collection are in the sample management plan provided to study sites. Blood chemistry
  • Vitamin B12 folate, iron, iron-binding capacity, ferritin Hematology Panel
  • Hemoglobin Differential Hematocrit Neutrophils Red blood cells Lymphocytes White blood cells Monocytes Red cell indices Basophils Platelet count Eosinophils Reticulocyte count Coagulation Panel
  • PT/aPTT Prothrombin time/activated partial thromboplastin time
  • laboratory tests may include:
  • Pregnancy testing serum human chorionic gonadotropin pregnancy testing, urine pregnancy testing
  • pregnancy testing (urinary human chorionic gonadotropin) is mandatory for all females from the age of sexual maturity, or for married females and, at the discretion of the investigator, for non-married females from the age of sexual maturity.
  • the blood draw schedule in the SOE Table is designed for patients with body weight equal or greater than 20 kg. It is expected that patients below 20 kg in weight will require reduction in blood-draw intensity.
  • a separate blood draw schedule will be provided for patients with body weight between 10 kg and 20 kg in the sample handling manual. For patients with body weight less than 10 kg, an order of priority of blood draws will be provided in the sample handling manual or kit instruction, and samples should be drawn in this order until the volume limit is reached.
  • the chemistry panel will have highest priority followed by full blood count and drug concentration.
  • Kits may be provided locally so that the chemistry panel may be taken locally to the patient without needing a site visit.
  • Drug concentration and ADA samples are to be collected prior to study drug administration.
  • drug concentration and ADA samples will be collected at or near the onset of the event for any additional analysis.
  • the week 4 PK sample may be analyzed in the ADA assay, provided there is sufficient volume.
  • the screening period may be extended to approximately 10 weeks for patients with extenuating circumstances.
  • the patients receiving the Polimab dosing regimen achieved improvements in albumin, total protein, vitamin B12, platelets, fecal a1AT, edema of face, edema of limbs, some suggestion of improvement in abdominal pain scores and bowel movement frequency; and an early indication of reduction in hospitalization days and a reduction in steroid use.
  • CHAPLE Albumin and total protein.
  • CHAPLE is characterized by a loss of serum protein, such as albumin, into the gastrointestinal tract resulting in hypoproteinemia, which can be complicated by edema, ascites, pleural and pericardial effusions, and malnutrition.
  • hypoproteinemia In healthy individuals, loss of protein through the gut epithelium has only a minor role in total protein metabolism.
  • Gastrointestinal (Gl) protein loss in CHAPLE can involve up to 60 % of the total albumin pool. Patients receiving the Dolimab regimen exhibited more normal levels of serum albumin and total protein suggesting alleviation of Gl protein loss.
  • albumin levels improved (increased to at or above the lower level of normal (LLN)) and remained at or above the LLN at all time points measured ( Figure 28(a)).
  • Monitoring of albumin levels for each patient prior to treatment demonstrated that albumin levels were historically below normal ( Figure 28(b)-(e)).
  • total protein levels improved (increased to between the lower level of normal (LLN) and upper level of normal (ULN)) and remained within this normal range at all time points measured (Figure 29).
  • Vitamin B12 Malabsorption and deficiency of vitamins, such as B12, have been observed in protein-losing enteropathy. Vitamin B12 levels in patients receiving the Polimab regimen improved over time. This is possibly due to alleviation of Gl malabsorption in CFIAPLE patients. These patients did not receive vitamin B12 supplementation. Shortly after initiation of treatment, vitamin B12 levels improved and the elevated levels were maintained at all time points measured ( Figure 30).
  • Alpha-1 -antitrypsin (A1A) is resistant to degradation by digestive enzymes and is, therefore, used as an endogenous marker for the presence of blood proteins in the intestinal tract. Patients receiving the Polimab regimen exhibited decreases in A1A. Shortly after initiation of treatment, fecal alpha-1 -antitrypsin concentration decreased in each patient and remained at the lower levels at all time points measured ( Figure 32).
  • CFIAPLE Facial and peripheral edema.
  • CFIAPLE is characterized by excessive loss of serum proteins into the gastrointestinal tract. This leads to reduced levels of serum proteins that, if severe, causes loss of fluid from the intravascular space and edema. There was evidence of alleviation of edema in patients receiving the Polimab regimen. Shortly after initiation of treatment, the severity (grade) of facial and peripheral edema generally decreased in the patients and remained at the lower levels at all time points measured ( Figure 33 and Figure 34).
  • Bowel movement frequency Patients suffering from CFIAPLE disease typically have diarrhea and excessive bowel movement frequency. These factors have significant impacts on patient quality of life and can lead to secondary medical conditions such as vitamin or electrolyte imbalances. There was evidence that patients on the Polimab regimen achieved an improvement in bowel movement frequency. Shortly after initiation of treatment there were early indication of a reduction in the frequency of bowel movements in the patients ( Figure 35).
  • the present invention thus, provides methods for:
  • edema e.g., facial or peripheral
  • steroids e.g., corticosteroids such as cortisone, hydrocortisone or prednisone
  • one or more doses e.g., weekly doses
  • one or more doses e.g., weekly doses
  • the antagonist antigenbinding protein that binds specifically to C5, subcutaneously (SC); or
  • one or more doses e.g., weekly doses
  • SC subcutaneously

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